 |
|
 |
| |
 |
1-alkyl-,1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols and related compounds |
| 5574164 |
1-alkyl-,1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols and related compounds
|
|
| Patent Drawings: | |
| Inventor: |
Tegeler, et al. |
| Date Issued: |
November 12, 1996 |
| Application: |
08/426,317 |
| Filed: |
April 21, 1995 |
| Inventors: |
Freed; Brian S. (Phillipsburg, NJ)
Hamer; Russell R. L. (Lebanon, NJ)
Merriman; Gregory H. (Fairfield, OH)
Rauckman; Barbara S. (Flemington, NJ)
Tegeler; John J. (Bridgewater, NJ)
|
| Assignee: |
Hoescht Roussel Pharmaceuticals Inc. (Somerville, NJ) |
| Primary Examiner: |
Chang; Ceila |
| Assistant Examiner: |
|
| Attorney Or Agent: |
Wittekind; Raymond R. |
| U.S. Class: |
546/175; 546/298; 546/314; 546/334; 548/247; 548/502; 549/76; 549/77; 568/426 |
| Field Of Search: |
546/175; 546/268; 546/334; 546/335; 548/247; 548/502; 549/76; 549/77; 568/426 |
| International Class: |
|
| U.S Patent Documents: |
5321165 |
| Foreign Patent Documents: |
|
| Other References: |
A Hajos, Acta Chimica Academiae Scientarum Hungaricae, 84, 471 (1975) published in Hungary & entitled "Synthesis of threo-anderythro-.beta.-o-tolylserine and their derivatives.".
S. Van Der Meer, et al., Recueil, 72, 236 (1953) published in the Netherlands and entitled "Chloramphenicol Analogues I"..
J. Morris & D. G. Wishka, Tetrahedron Letters, 29, 143 (1988) published in Great Britain and entitled "Synthesis of Novel Antagonists of Leukotriene B.sub.4 "..
K. Sonogashira, et al. Tetrahedron Letters, 50, 4467 (1975) published in Great Britin and entitled "A Convenient Synthesis of Acetylenes: Catalytic Substitutions of Acetylenic Hydrogen with Bromoalkenes, Iodoarnes, and Bromopyridines"..
J. E. Parks, et al., Inorganic Chemistry, 10, 2472 (1971) published in the United States of America and entitled "Three-Dimensional Macrocyclic Encapsulation reactions, II. Synthesis and Properties of Nonoctahedral Clathro Chelates Derived fromTris(2--aldoximo--6--pyridyl)phosphine and Boron Trifluoride or Tetrafluoroborate"..
E. L. Smith and J. J. Tegeler, Annual Reports in Medicinal Chemistry, 24, 13 (1989) published in the United States of America and entitled "Chapter 19. Advances in Dermatology"..
A. K. Gupta, et al., The Journal of Investigative Dermatology, 91, 486 (1988) published in the United States of America and entitled "Sphingosine Inhibits Phorbol Ester-Induced Inflammation, Ornithine Decarboxylase Activity, and Activation ofProtein Kinase C in Mouse Skin"..
Ng. Ph. Buu Hoi, et al., Chemical Abstracts, 45, 9005i (1951) published in the United States of America and entitled "Three new analogs of chloramphenicol "..
H. M. Crooks, Jr., et al., Chemical Abstracts, 46, 9602c (1952) published in the United States of America and entitled "Diarylphenylpropaneaminodiols"..
Parke, Davis & Co., Chemical Abstracts, 48, 8823g (1954) published in the United States of America and entitled "Organic amino diols"..
Parke, Davis & Co., Chemical Abstracts, 47, 3347d (1952) published in the United States of America and entitled "Amino diols"..
H. M. Crooks, Jr., et al., Chemical Abstracts, 45, 633a (1951) published in the United States of America and entitled "(Nitrophenyl)acylaminoalkane diols"..
L. M. Long and N. D. Jenesel, Chemical Abstracts, 45, 9564b (1951) published in the United States of America and entitled "Furan compounds"..
E. C. Hermann, Chemical Abstracts, 50, 5760c (1956) published in the United States of America and entitled "Thienyl amido--1, 3--propanediols"..
Duke Univ., Derwent 88-091694113 published May 25, 1988 in Great Britain and entitled "Inhibition of protein kinase C with amphipathic long-chain base-esp. with sphingosine, for treating asthma, inflammation, psoriasis or tumour metastasis.".
M. Miyoshi, et al., Chemical Abstracts, 92, 198778a (1980) published in the United States of America and entitled ".beta.-Hydroxyamino acids"..
F. A. Arena, et al., Chemical Abstracts, 89, 59826q (1978) published in the United States of America and entitled "Structure-activity relations in acetylcholinesterase reactivators inhibited by phosphoric esters. XII. Hydroxyiminomethylalkylpiridinemethiodides"..
S. Nimkar, et al., Tetrahedron Letters, 29, 3037 (1988) published in Great Britain and entitled "A Stereoselective Synthesis of Sphingosine, A Protein Kinase C Inhibitor"..
Y. Gao, et al., Journal of the American Chemical Society, 109, 5765 (1987) published in the United States of America and entitled "Catalytic Asymmetric Epoxidation and Kinetic Resolution: Modified Procedures Including in Situ Derivatization"..
S. Knapp, et al., Journal of Organic Chemistry, 55, 5700(1990) published in the United States of America & entitled "Amino Alcohol and Amino Sugar Synthesis by Benzoylcarbamate Cyclization"..
P. Garner & J. M. Park, Journal of Organic Chemistry, 52, 2361(1987) published in the United States of America & entitled "The Synthesis and Configurational Stability of Differentially Protected .beta.--Hydroxy--.alpha.--amino Aldehydes"..
D. P. Schumacher, et al, Journal of Organic Chemistry, 55, 5291 (1990) published in the United States of America & entitled "An Efficient Synthesis of Florfenicol"..
D. A. Evans & A. E. Weber, Journal of the Am. Chem. Soc., 109, 7151 (1987) published in the United States of America & entitled "Synthesis of the Cyclic Hexapeptide Echinocandin D. New Approaches to the Asymmetric Synthesis of .beta.-Hydroxy.alpha.-Amino Acids"..
Y. Nishizuka,Nature,308, 693 (1984) published in Great Britain & entitled "The role of protein kinase C in cell surface signal transduction and tumour promotion"..
L. Hegemann, et al., Archives of Dermatological Research,281,561 (1990) published in Germany & entitled "Inhibitors of proteinkinase C express antiproliferative properties in keratinocytes in vitro"..
L. Hegemann and G. Mahrle in "Pharmacology of the Skin", H. Muktar, Ed; CRC Press, Ann Arbor, Michigan, pp. 357 to 368, 1992..
J. J. Tegeler, et al., Chemical Abstracts, published in the United States of America and entitled "Preparation of Heteroarylaminoalkanols"..
Zhang et al. "A convenient synthesis of fluoroaromatic acetylene derivatives"CA 113:114702n (1990)..
Villemin et al. "Pd-homogeneous and supported catalysis: synthesis of functional acetylenics and cyclisation to heterocyclces"Heterocycles v. 209, 1255-1261 (1989).. |
|
| Abstract: |
Novel 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, intermediates and processes for the preparation thereof, and methods of reducing inflammation and cell proliferation, and relieving memory dysfunction, and inhibiting bacterial and fungal growth are disclosed. |
| Claim: |
We claim:
1. A process for the preparation of a compound of the formula RCHO wherein R is
wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.tbd.C or ##STR62## wherein m is 9 to 15 and n is 0 to 12; R.sup.40 is alkyl or a group of the formula ##STR63## wherein W is as below; W and X are independently hydrogen, loweralkyl, loweralkoxy,halogen, or trifluoromethyl; with the proviso that when R is ##STR64## X is not hydrogen or loweralkyl Z is O; and A is O or S; which comprises contacting a compound of the formula RCHO wherein R is ##STR65## wherein R.sup.40, X, A and Z are as aboveand Y is halogen; with the compound of the formula CH.sub.3 (CH.sub.2).sub.m C.tbd.CH or ##STR66## wherein W, m and n are as above in the presence of bis(triphenylphosphine)palladiumdichloride and cuprous iodide and an acid acceptor.
2. The process of claim 1 wherein the acid acceptor is a di- or tertiary amine.
3. The process of claim 1 wherein the tertiary amine is triethylamine.
4. The process of claim 1 wherein a solvent is employed.
5. The process of claim 1 wherein the solvent is tetrahydrofuran. |
| Description: |
The present invention relates to 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols. More particularly,the present invention relates to 1-alkyl-, 1-alkenyl-, and 1-alkylnylaryl-2-amino-1,3-propanediols of formula 1.
wherein R is ##STR1## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.XI.C, CH.sub.3 (CH.sub.2).sub.m CH.dbd.CH, CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2, ##STR2## wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen,hydroxy, alkyl, alkoxy, halogen, or trifluoromethyl, or ##STR3## wherein R.sup.23 is loweralkyl; Z is S, O, or C.dbd.O; and A is S or O; R.sup.1 is hydrogen, alkyl, Si(R.sup.23).sub.2 C(R.sup.23).sub.3 wherein R.sup.23 is alkyl, ##STR4## wherein R.sup.24is alkyl or ##STR5## wherein R.sup.6 is hydrogen alkyl, alkoxy, N(R.sup.21).sub.2 wherein R.sup.21 is hydrogen, alkyl, or ##STR6## wherein W is as above, or ##STR7## R.sup.2 is hydrogen or alkyl; R.sup.3 is hydrogen, alkyl or ##STR8## wherein R.sup.6 isas above or NHR.sup.27 wherein R.sup.27 is alkyl; R.sup.35 is ##STR9## wherein R.sup.36 is alkyl; R.sup.4 is ##STR10## wherein R.sup.7 is hydrogen or alkyl, C(R.sup.25).sub.2 OR.sup.8 wherein R.sup.8 is hydrogen, alkyl, or ##STR11## wherein R.sup.6 is asabove and R.sup.25 is hydrogen or alkyl; R.sup.40 is alkyl or a group of the formula ##STR12## wherein W is as above; R.sup.1 and R.sup.8 taken together with the oxygen to which they are attached form a group of the formula ##STR13## wherein R.sup.9 andR.sup.10 are independently hydrogen or alkyl; R.sup.2, R.sup.3 and R.sup.4 taken together with the nitrogen and oxygen to which they are attached form a group of the formula ##STR14## wherein W is as above; R.sub.3 and R.sub.4 taken together with thenitrogen and oxygen atoms to which they are attached form a group of the formula ##STR15## wherein R.sup.2 is as above; R.sup.2 and R.sup.3 taken together with the nitrogen atom to which it is attached form a group of the formula ##STR16## wherein W isas above; R.sup.3 and R.sup.4 taken together with the nitrogen and oxygen atoms to which they are attached form a group of the formula ##STR17## wherein R.sup.2 is as above and R.sup.25 is alkyl; R.sup.1, R.sup.2 and R.sup.3 taken together with thenitrogen and oxygen atoms to which they are attached form a group of the formula ##STR18## wherein R.sup.26 is alkyl; the optical isomers thereof, or the pharmaceutically acceptable salts thereof, which are useful for reducing inflammation by virtue oftheir ability to inhibit protein kinase C and thus indicated for the treatment of psoriasis and other skin disorders, for inhibiting tumor or neoplastic cell growth by virtue of their ability to reduce cell proliferation and thus indicated in cancertherapy, and relieving memory dysfunction and thus indicated in the treatment of Alzheimer's disease, and as antibacterial and antifungal agents, alone or in combination with adjuvants.
Preferred 2-amino-1,3-propanediols of the present invention are those wherein R is ##STR19## R.sup.1, R.sup.2, and R.sup.3 are hydrogen and R.sup.5 is CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2 or ##STR20## Also preferred are compounds wherein Ris ##STR21## R.sup.1 and R.sup.2 are hydrogen; R.sup.4 is ##STR22## and R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.XI.C.
The present invention also relates to compounds of the formulas
wherein R is ##STR23## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.XI.C, CH.sub.3 (CH.sub.2).sub.m CH.dbd.CH, CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2, or ##STR24## wherein m is 3 to 15, n is 0 to 12, W and X are independently hydrogen,alkyl, alkoxy, halogen, or trifluoromethyl and Z is S or O; A is S or O; R.sup.40 is alkyl or a group of the formula ##STR25## wherein W is as above; ##STR26## wherein R is ##STR27## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.XI.C, CH.sub.3(CH.sub.2).sub.m CH.dbd.CH, CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2, or ##STR28## wherein m is 3 to 15, n is 0 to 12, R.sup.16 is hydrogen or a group of the formula ##STR29## W and X are independently hydrogen, alkyl, alkoxy, halogen, ortrifluoromethyl, and Z is 0; and
wherein R is ##STR30## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.XI.C, CH.sub.3 (CH.sub.2).sub.m CH.dbd.CH, CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2, ##STR31## wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen,loweralkyl, loweralkoxy, halogen, or trifluoromethyl, Z is S, O, or C.dbd.O; and A is S or O, and R.sup.4 is ##STR32## wherein R.sup.7 is hydrogen or loweralkyl, C(R.sup.25).sub.2 OR.sup.8 wherein R.sup.8 is hydrogen, loweralkyl, or ##STR33## is asabove; and ##STR34## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.XI.C, CH.sub.3 (CH.sub.2).sub.m CH.dbd.CH, CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2, ##STR35## wherein m is 3 to 15, n is 0 to 12, and W and X are independently hydrogen, loweralkyl,loweralkoxy, halogen, or trifluoromethyl which are useful as intermediates for the preparation of the present 2-amino-1,3-propanediols.
Also included as intermediates for the preparation of the present 2-amino-1,3-propanediols are oxazolidinones of the formula
wherein R is ##STR36## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.tbd.C, CH.sub.3 (CH.sub.2).sub.m CH.dbd.CH, CH.sub.3 (CH.sub.2).sub.m CH.sub.2 CH.sub.2, ##STR37## wherein m is 3 to 25, n is 0 to 12, and W and X are independently hydrogen,alkyl, alkoxy, halogen, or trifluoromethyl, Z is S, O, or C.dbd.O; and A is S or O; R.sup.1 is hydrogen or ##STR38## wherein R.sup.6 is hydrogen, alkyl, alkoxy, or ##STR39## R.sup.18 is halogen or N.sub.3 ; and R.sup.19 is a group of the formula##STR40## wherein W is hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl; or a group of the formula ##STR41## wherein R.sup.20 is loweralkyl.
As used through the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 10 carbon atoms. Examples of alkyl groups are methyl, ethyl, 1-propyl,2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl, 3-nonyl, 4-decyl and the like. The term "alkanol" refers to a compound formed by a combination of an alkyl group and hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 2,2-dimethylethanol, hexanol, octanol, decanol and the like. The term "alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, aceticacid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid and the like. The term "halogen" refers to a member of the family fluorine, chlorine, bromine, or iodine. The term "alkanoyl" refers to the radical formed byremoval of the hydroxyl function from an alkanoic acid. Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl and the like. The term "lower" as applied to any of the aforementioned groups refers toa group having a carbon skeleton containing up to and including 8 carbon atoms.
The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipodes may be prepared from the corresponding racemic forms by standard optical resolutiontechniques, involving, for example, the separation of diastereomeric salts of those instant compounds characterized by the presence of a basic amino group and an optically active acid, those instant compounds characterized by the presence of a carboxylicacid group and an optically active base, or by synthesis from optically active precursors.
The present invention comprehends all optical isomers and racemic forms thereof and all geometric isomers of the compounds disclosed and claimed herein. The formulas of the compounds shown herein are intended to encompass all possible geometricand optical isomers of the compounds so depicted.
The compounds of the present invention that have adjacent chiral centers exist as diastereomers and are distinguished as the erythro- and threo-isomers. The erythro diastereomers are those that become meso, i.e., optically inactive, by virtue ofhaving an element of symmetry in one of the possible conformations, when one of the dissimilar substituents is replaced by the other. The threo diastereomers are those that remain enantiomeric, i.e., optically active, by virtue of lacking an element ofsymmetry in one of the possible conformations, when one of the dissimilar substitutents is replaced by the other. For example, replacement of the amino group of an erythro-2-amino-1,3-propanediol 9a of the present invention by a hydroxyl group creates ameso-1,2,3-propanetriol 9b, having a plane of symmetry through the carbon backbone of the molecule, as shown below, ##STR42## and replacement of the amino group of a threo-2-amino-1,3-propanediol 9c of the present invention by a hydroxy group creates anenantiomer 9d, lacking an element of symmetry in all conformations, one of which is 9d. ##STR43##
The chirality of the enantiomeric compounds of the present invention, prepared by asymmetric induction, is designated by the symbols "R" and "S" and is determined by application of the sequence-rule of Cahn-Ingold- and Prelog (see R. S. Cahn, C.Ingold, and v. Prelog, Angewandte Chemie, International Edition English, 5, 385 (1966) and 5, 511 (1966). Thus, for example, the handedness of the chiral centers at the 2- and 3-positions of the 2-amino-1,3-propanediol 9e ##STR44## prepared from(4S)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone, is designated 2R (right) and 3S (left). The centers of the enantiomeric 2-amino-1,3-propanediol 9f, ##STR45## prepared from the enantiomeric (4R)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone, isdesignated 2S and 3R.
The novel 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are prepared by the processes illustrated in Reaction Schemes A, B, and C for the pyridine series, D to L for the thiophene series, and M and Nfor the phenyl series, having an aralkyl side-chain. The transformations shown therein are applicable to the preparation of compounds of the invention wherein the aryl group is, among others, substituted and unsubstituted phenyl, furyl, thienyl,isoxazolyl, isothiazolyl, and pyrrolyl, thiazolyl, and oxazolyl, having a 1-alkyl, 1-alkenyl, or 1-alkynyl-side chain.
To prepare a 1-alkynylpyridinyl-2-amino-1,3-propanediol 7 wherein W and X are hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, a pyridinylcarboxaldehyde 2 wherein W and X are as above and Y is halogen is condensed with an amidomalonic acidester 3 wherein R.sup.11 and R.sup.12 are alkyl to provide an alkyl pyridinylpropionate 4 wherein R.sup.11, R.sup.12, X, and Y are as above, which is alkynylated to alkynylpyridine 5 wherein R.sup.11, R.sup.12, W and X are as above and n is 3 to 15 and,in turn, reduced to pyridinyl-1,3-propanediol 6 wherein R.sup.12, W, and X are as above and hydrolyzed to 7.
The condensation of carboxaldehyde 2 and malonate 3 is conducted in an ethereal solvent in the presence of a tertiary amine. Among ethereal solvents there may be mentioned diethyl ether, methyl tert-butyl ether, 1,2-dimethyoxyethane,2-methoxyethyl ether, dioxane, and tetrahydrofuran. Among tertiary amines there may be mentioned pyridines (pyridine, picoline, lutidine, and collidine) and trialkylamines (trimethylamine, triethylamine, and tripropylamine). Tetrahydrofuran andtriethylamine are the preferred solvent and tertiary amine, respectively, While the condensation temperature is not critical, the reaction is preferably performed at about ambient temperature (25.degree. C.), although reduced temperatures (about0.degree. C. to about 25.degree. C.) or elevated temperatures (about 25.degree. C. to the boiling point of the reaction mixture) may be employed.
The alkynylation is performed by treating a halopyridine 4 with an alkyne 13 ##STR46## wherein W and n are as above in an acid acceptor, e.g., a di- or trialkylamine, such as, diethylamine, dipropylamine, trimethylamine, triethylamine, ortripropylamine, in the presence of bis(triphenylphosphine)palladium dichloride/cuprous iodide at a temperature of about 0.degree. to about 75.degree. C. Triethylamine is the preferred acceptor. A temperature of about 50.degree. to 60.degree. C. isthe preferred alkynylation temperature. An ethereal solvent may be employed. Ethereal solvents include diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 2-methoxyethyl-ether, dioxane, and tetrahydrofuran. Tetrahydrofuran is the preferredsolvent.
The reduction of an alkyl pyridinylpropionate 5 to a propanediol 6 is accomplished by means of an alkali borohydride in an ethereal solvent at a reduction temperature within the range of about 0.degree. to about 50.degree. C. Included amongalkali borohydrides are calcium borohydride, lithium borohydride, potassium borohydride, and sodium borohydride. Included among ethereal solvents are diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, andtetrahydrofuran. A reducing system of lithium borohydride or calcium borohydride in tetrahydrofuran at a temperature of from about 0.degree. to 25.degree. C. is preferred.
The hydrolysis of a carboxamide 6 to an aminodiol 7 may be carried out by conventional hydrolysis techniques. For example, carboxamide 6 may be hydrolyzed by an alkali metal hydroxide, i.e., lithium hydroxide, sodium hydroxide, or potassiumhydroxide, in an aqueous alkanol, i.e., methanol, ethanol, or 1- or 2-propanol, at a hydrolysis temperature of about 0.degree. C. to about 100.degree. C.
To prepare a 1-alkylpyridinyl-2-amino-1,3-propanediol 9 wherein W, X, and m are as hereinbeforedescribed, a 1-alkynylpyridinyl-2-amido-1,3-propanediol 6 is hydrogenated to a 1-alkylpyridinyl-2-amido-1,3-propanediol 8, which is converted to a1-alkylpyridinyl-2-amino-1,3-propanediol 9.
The hydrogenation is effected by treating an alkyne 6 with hydrogen at about atmospheric pressure to about 60 psi, a pressure of about 40 psi being preferred, in the presence of a metal catalyst, e.g., platinum, palladium, rhodium, or ruthenium,unsupported or supported on carbon or calcium carbonate, palladium-on-carbon being preferred, in an alkanol, e.g., methanol, ethanol, or 1- or 2-propanol, ethanol being preferred, at a hydrogenation temperature of about 25.degree. to about 50.degree. C., a temperature of about 25.degree. C. being preferred.
The conversion of pyridinylamidodiol 8 to pyridinylaminodiol 9, i.e., the hydrazinolysis of 8, is conducted with hydrazine, free or in its hydrated form, in an alkanol such as, for example, methanol, ethanol, or 1- or 2-propanol, at a temperatureof from about 25.degree. C. to the reflux temperature of the reaction mixture. Ethanol is the preferred solvent. A hydrazinolysis temperature of about the reflux temperature of the reaction mixture is also preferred.
Alternatively, entry into the 1-alkynyl- and 1-alkylpyridinyl-2-amino-1,3-propanediol systems, i.e., systems of formulas 7 and 9, respectively, wherein W, X, and m are as hereinbeforedescibed may be achieved by alkynylation ofpyridinylcarboxaldehyde 2 wherein W, X, and Y are as above to alkynylpyridinylcarboxaldehyde 10 wherein W, X, and m are as above followed by conversion of pyridinylcarboxaldehyde 10 to alkyl pyridinylpropionate 5 wherein R.sup.11, R.sup.12, W, X, and mare as above and hydrogenation of an alkynylpyridine 5 wherein R.sup.11, R.sup.12, W, X, and m are as above to 11 wherein R.sup.11, R.sup.12, W, X, and m are as above. The alkynylation, conversion, and hydrogenation, i.e., the transformations of 2 to 5and 11, via 10, are accomplished by processes substantially similar to the corresponding transformations of 4 to 5, 2 to 4, and 6 to 8.
Alkyl 1-alkylpyridinylpropionate 11 wherein R.sup.11, R.sup.12, W, X, and m are as above may be reduced to 1-alkyl pyridinylpropanediol 8 by the process essentially the same as that employed for the reduction of alkyl pyridinylpropionate 5 topropanediol 6.
Entry into the 1-alkynylpyridinyl-2-amino-1,3-propanediol series, i.e., the series encompassing compounds of formulas 5, 6, and 7, is also attained by reducing an alkyl pyridinylpropionate 4 wherein R.sup.11, R.sup.12, W, X and Y are ashereinbeforedescribed to a pyridinylpropanediol 12 and alkynylating a pyridinyldiol 12, so obtained, to alkynylpyridinyldiol 6. As described above, amidopropanediol 6 is converted to amino propanediol 7 by hydrolysis. Similarly, the reduction of 4 to12 and the alkynylation of 12 to 6 are performed by processes substantially the same as those utilized for the conversion of 5 to 6 and 4 to 5.
Derivatives of an alkynylpyridinyl-2-amino-1,3-diol 7 are prepared from amidopropanediol 6 by acylation of 6 wherein R.sup.12, W, X, and m are as hereinbeforedescribed to an amidodiacyloxypropane 15 wherein R.sup.12, R.sup.13, R.sup.14, W, and mare as hereinbeforedescribed with, for example, an alkanoic acid anhydride such as acetic anhydride in the presence of triethylamine and 4-dimethylaminopyridine to 15, and dioxanylation of 6 to amidodioxane 14 wherein R.sup.12, R.sup.15, R.sup.16, W, X,and m are as hereinbeforedescribed with, for example, 2,2-dimethoxypropane in the presence of para-toluene sulfuric acid. Hydrolysis of 15 as described for the conversion of 6 to 7 provides aminopropanediol 7. An amidodiacyloxypropane 15 is selectivelyhydrolyzed to an amidodihydroxy propane 20 by, for example, an alkali metal carbonate such as lithium, sodium, or potassium carbonate in an alkanol such as methanol, ethanol, or 2-propanol. Potassium carbonate in methanol is the preferred hydrolysismedium. The hydrolysis proceeds readily at ambient temperature. Elevated temperatures to the reflux temperature of the hydrolysis medium may be employed.
Acyl derivatives of amidopropanediol 12 wherein R.sup.2, X, and Y are as hereinbeforedescribed are prepared by treating 12 with an alkanoic acid anhydride under the conditions for the conversion of 6 to 15.
To prepare a 1-alkenyl-2-amino-1,3-propanediol 17 wherein W, X, and m are as hereinbeforedescribed a 1-alkynyl-2-amino-1,3-propanediol 6 wherein R.sup.12, W, X, and m are as above is hydrogenated to a 1-alkenyl-2-amino-1,3-propanediol 16 whereinR.sup.12, W, X, and m are as above and the configuation of the hydrogen atoms of the carbon-to-carbon double bond is cis, which is hydrolyzed to 17 wherein W, X, and m are also as above.
To fabricate an N,O,O-tribenzyloxycarbonyl-2-amino-1,3-propane 18 wherein R.sup.15 is ##STR47## and 2-amino-1,3-propanediol 9 is treated with N-benzyloxycarbonyloxysuccinimide 20 ##STR48## in the presence of a tertiary amine, e.g., triethyl aminein an ethereal solvent, e.g., tetrahydrofuran at about ambient temperature.
To synthesize a 2-amino-1,3-propanediol 19, a 1,3-diacyloxy-2-propanylacetamide 13 is hydrolyzed by hydrazine hydrate in the presence of ethanol according to the procedure for the conversion of 8 or 9.
Generally, the ultimate 1-alkylaryl-2-amino-1,3-propanediols of the present invention are prepared from 1-alkynylarylcarboxaldehydes. See Reaction Scheme A for the conversion of 10 to 9 in the pyridine series. In the isoxazole series, theultimate 1-alkylisoxazolyl-2-amino-1,3-propanediols may be prepared, for example, from a 5-(1-alkyl)-3-isoxazolecarboxaldehyde 21 wherein R.sup.5 is dodecyl. ##STR49##
A 3-isoxazolecarboxaldehyde 21 wherein R.sup.5 is dodecyl, in turn, is synthesized, for example, by condensing 1-nitrotridecane with O-trimethylsilylpropynol in the presence of phenylisocyanate and triethylamine followed tetrabutylammoniumfluoride to afford isoxazolemethanol 22 ##STR50## wherein R.sup.5 is dodecyl, which is oxidized by oxalyl chloride:dimethylsulfoxide to 21.
To prepare a 2-alkoxycarbonylamino-1,3-propanediol, for example, 1-alkynyl-2-t-butyloxycarbonylamino-1,3-propanediol 6 wherein R.sup.12 is OC(CH.sub.3).sub.3, a 1-alkynyl-2-amino-1,3-propanediol 7 is acylated with di-t-butyldicarbonate in thepresence of a base such as sodium bicarbonate in a halocarbon solvent such as chloroform at an elevated temperature of about 60.degree. C.
To prepare a 2-dialkylamino-1,3-propanediol, for example, a 1-alkenyl-2-dimethylamino-1,3-propanediol 23, a 1-alkenyl-2-amino-1,3-propanediol 17 is reductively alkylated with formaldehyde such as formalin in the presence of a reducing agent suchas sodium cyanoborohydride in a solvent such as acetonitrile at ambient temperature.
Additional N-substituted 2-amino-1,3-propanediols of the present invention are prepared by acylation of an aminodiol, for example, a thienylaminodiol 30. Thus, treatment of amino 30 with an isocyanate 34
wherein R.sup.27 is as hereinbeforedescribed affords a urea 31 wherein R.sup.5, R.sup.27, and X are as hereinbeforedescribed, with an acyl halide 35
wherein R.sup.6 is as hereinbeforedescribed affords an amide 32 wherein R.sup.6 is as hereinbeforedescribed and Hal is chloro or bromo, and with haloformate 36
wherein R.sup.28 and Hal are as hereinbeforedescribed affords a urethane 33. More specifically, treatment of amine 30 with an isocyanate 34 in a dipolar aprotic solvent (e.g., dimethylacetamide, dimethylformamide, hexamethylphosphoramide, ordimethylsulfoxide) in the presence of an acid acceptor (e.g., pyridine, 4-dimethylaminopyridine, triethylamine, or tripropylamine), or in a halocarbon (dichloromethane, trichloromethane, or 1,1- or 1,2-dichloroethane) affords urea 31. Similarly,treatment of amine 30 with a carboxylic acid halide 35 or a haloformate 36 in a dipolar aprotic solvent and acid acceptor such as those mentioned above provides amide 32 and urethane 33, respectively. While the reaction temperature at which theacylations are preformed are not narrowly critical, the transformations proceed at a reasonable rate at a temperature between about -10.degree. C. and about ambient temperature. A reaction temperature of about -10.degree. C. or about ambienttemperature is preferred. The preferred dipolar aprotic solvent is dimethylformamide; the preferred halocarbon is dichloromethane.
The conversion of an N-acyl-2-amino-1,3-diol 6 to a 5-acylamino-2,2-dialkyl-1,3-dioxane 14 is depicted in Reaction Scheme B and described hereinbefore in the specification. A 5-amino-2,2-dialkyl-1,3-dioxane 37 is prepared from 2-amino-1,3-diol30 by employing substantially the same conditions as hereinbeforementioned. A cosolvent such as a halocarbon, i.e., dichloromethane may be utilized. See Reaction Scheme E.
To prepare an oxazolinylmethane 38, a 2-amino-1,3-diol 30 is condensed with a benzonitrile 39 ##STR51## wherein W is an hereinbeforedescribed in the presence of a base, for example, an alkali metal carbonate such as lithium, sodium, or potassiumcarbonate, potassium carbonate being preferred, at an elevated temperature within the range of about 80.degree. C. to about 140.degree. C., a condensation temperature of about 110.degree. C. being preferred, in a high boiling solvent system consistentwith the reaction temperature chosen to provide a reasonable rate of reaction. Included among such solvent systems are mixtures of trihydric alcohols, e.g., glycerol, and dihydric alcohols, e.g., ethylene glycol, suitable for maintaining a condensationtemperature of about 110.degree. C.
To protect the arylic hydroxyl group, i.e., the hydroxyl group at the 1-position of the propane chain of an amidic propanoic ester for envisioned transformations, compound 40, for example, is treated with a silyl halide 43 ##STR52## whereinR.sup.29 is alkyl and Hal is chloro or bromo, preferably t-butyldimethylsilyl chloride, in the presence of a acid acceptor such as an imidazole, including imidazole itself, in a dipolar aprotic solvent comprising dimethylacetamide, dimethylformamide,hexamethylphosphoramide, or dimethylsulfoxide, dimethylformamide being preferred, to provide a silyloxy ester 41. The introduction of the protecting group proceeds readily at ambient temperature; however, reduced or elevated temperatures within therange of about 10.degree. C. to 40.degree. C. may be employed. Silyloxy ester 41 is then reduced to silyloxy carbinol 42 by processes such as those hereinbeforedescribed to the conversion of 5 to 6.
The transformations depicted in Reaction Schemes A to E refer to conversions in both the erythro- and threo-series. See pages 5 and 6 for a discussion of this nomenclature. threo-Compounds are prepared from the corresponding erythro-anologs bythe conversions shown in Reaction Scheme F. Treatment of an erythro-hydroxyamide 43 with triphenylphosphine and diethyl azodicarboxylate in an ethereal solvent such as, e.g., tetrahydrofuran, provides, with inversion at the arylic position, athreo-carbalkoxyoxazoline 44, which is hydrolyzed under acidic conditions, i.e., aqueous acetic acid, at a hydrolysis temperature within the range of about ambient temperature to about 75.degree. C., a reaction temperature of about 50.degree. C. beingpreferred, to a threo-hydroxyester 45. Reduction of the ester group of an amidic ester 45 with, for example, lithium borohydride, as hereinbeforedescribed for the conversion of 5 to 6, affords a threo-amidic diol, which is hydrolyzed by, for example,aqueous sodium hydroxide to a threo-aminodiol 47.
To fabricate a dialkylaminoalkoxypropanol 49 wherein R.sup.15 is alkyl and R and X are as hereinbeforedescribed, an aminodiol 30 is N-dialkylated by the process for the conversion of 17 to 23 to provide a dialkylaminodiol 48, which is O-alkylatedto provide a dialkylaminoalkoxycarbinol 49. The O-alkylation is accomplished by treating 48 with an alkali metal hydride such as lithium, sodium, or potassium hydride, potassium hydride being preferred, in a dipolar aprotic solvent (e.g.,dimethylacetamide, dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide) to form an alkoxy anion, which in turn is treated with a dialkyl sulfate 51
wherein R.sup.15 is as hereinbeforementioned at ambient temperature to form an alkoxycarbinol 49.
An isoindoledione 50 is prepared by heating an aminodiol 30 with a phthalic anhydride 52 ##STR53## wherein W is as hereinbeforedesribed at an elevated temperature of about 100.degree. C.
Various other N-substituted derivatives of a 2-amino-1,3-propanediol 30 are prepared by the processes shown in Reaction Schemes H and I. Thus, alkylation of a oxazolinylmethanol 38 with an alkyl halide 57
wherein R.sup.15 is as hereinbeforedescribed and Hal is bromo, chloro, or iodo followed by hydrolysis affords an alkylaminopropanediol 56 wherein R.sup.15 is alkyl. The alkylation is performed in a dipolar aprotic solvent such as, for example,dimethylsulfoxide at about ambient temperature. The hydrolysis is effected without isolation of the alkylation product by means of an aqueous alkali metal hydroxide such as, for example, sodium hydroxide at a temperature within the range of aboutambient temperature to about 100.degree. C., a hydrolysis temperature of about 60.degree. C. being preferred.
In contrast to the abovementioned process, alkylation of 38 with an alkyl halide 57 provides a methoxymethyloxazoline 53, which is hydrolyzed first to a methoxybenzamide 54 and then to a methoxyamine 55. The alkylation is carded out by formingthe alkoxide ion of 38 of means of an alkali metal hydride such as sodium hydride in a dipolar aprotic solvent such as dimethylformamide at about ambient temperature to provide an O-alkoxymethyl oxazoline 53.
The first hydrolysis, i.e., the conversion of an oxazoline 53 to an amide 54 is accomplished under acidic conditions, for example, by an aqueous carboxylic acid such as aqueous acetic acid at a hydrolysis temperature of about 25.degree. to about75.degree. C. The preferred hydrolysis temperature is about 50.degree. C. The second hydrolysis is effected by an aqueous alkali metal hydroxide such as aqueous sodium hydroxide in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or1,1-dimethylethanol) at a hydrolysis temperature with in the range of about 50.degree. to about 90.degree. C. Ethanol is the preferred solvent. A hydrolysis temperature of about 70.degree. C. is the preferred.
Additional N-substituted derivatives of a 2-aminopropanediol 30 are prepared by the methods outlined in Reaction Scheme I. Thus, acylation of a 1,3-propanediol 33 by the procedure hereinbeforedescribed for the conversion of 6 to 15 gives a1,3-dialkanoyloxycarbamate 58 which is alkylated and hydrolyzed to a 1,3-dihydroxy N-alkylcarbamate 59. The alkylation is achieved by the procedure described for the conversion of 48 to 49. The hydrolysis of 58 by aqueous potassium carbonate in analkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol). Methanol is preferred; a hydrolysis temperature of about ambient temperature is also preferred.
Similarly, reduction of a dihydroxyamide 60 with an alkali metal aluminum hydride, for example, lithium aluminum hydride in an ethereal solvent, for example, diethyl ether/tetrahydrofuran at about ambient temperature affords anN-ethyldihydroxyamine 61, which is acylated with a carboxylic acid anhydride 64
wherein R.sup.31 is alkyl in the presence of a base, for example, a mixture of triethylamine and 4-dimethylaminopyridine in an ethereal solvent, for example, tetrahydrofuran to provide an O,O-dialkanoyloxyamide 62. An amide 62 is then hydrolyzedunder basic conditions, for example, potassium carbonate in methanol to give a dihydroxy-N-ethylamide 63.
The presence of chiral centers at positions 1 and 2 of the present 2-amino-1,3-propanediols, and derivatives thereof, provides an opportunity to prepare stereochemical isomers of the ultimate products and thereby adduce whether the enantiomers ofthis series of compounds exhibit different pharmacological properties, as has been generally deserved in the art. Significantly, desirable properties generally reside in an enantiomer, while adverse properties inhere in the other.
To gain access to the enantiomers of the present 2-amino-1,2-propanediols, and derivatives thereof, a thiophene 64 wherein R is as hereinbeforedescribed is condensed with a chiral 1,1-dialkylalkyl-4-formyl-2,2-dialkyl-3-oxazolidinecarboxylate 70##STR54## wherein R.sup.32 is alkyl, the preparation of which is described in G. Garner and J. M. Park, Journal of Organic Chemistry, 52, 2761 to 2367 (1987), to afford a mixture of diastereomeric hydroxyoxazolidines 65a and 65b, i.e., erythro- andthreo-isomers, wherein R.sup.32 is as above, which is acylated to a mixture acyloxyoxazolidines 66a and 66b, separated into a pure enantiomer 66b, and hydrolyzed to an enantiomeric hydroxyoxazolidine 67, then to an N-acyloxydiol 68, and finally to anenantiomeric 2-amino-1,3-propanediol 69.
The condensation is effected by treating a thiophene 64 with a strong base, for example, an alkyl- or arylalkali metal such as n-butyllithium, sec-butyllithium or phenyllithium in an ethereal solvent such as 1,2-dimethoxyethane,2-methoxyethylether, dioxane, or tetrahydrofuran, followed by adding, in this case, chiral oxazolidine 70, also in an ethereal solvent to the salt so formed to a afford a mixture of the erythro- and threo-hydroxyoxazolidines 65a and 65b. Thecondensation is generally carried out at a reduced temperature in the range of about -100.degree. to -50.degree. C., a reaction temperature of about -78.degree. C. being preferred.
The acylation is readily achieved by processes hereinbeforedescribed for the conversion of 6 to 15, namely, by treating a mixture of 65a and 65b with a carboxylic acid anhydride 71
wherein R.sup.32 is alkyl in an ethereal solvent (e.g., tetrahydrofuran) in the presence of a base or combination of bases (e.g., triethylamine and/or 4-dimethylaminopyridine) at room temperature to yield a mixture of O-acyloxyoxazolidines 66aand 66b.
The separation of the diastereomeric mixture is accomplished by selective crystallization techniques or chromatographic methods, for example, thin-layer, column, including high pressure and flash chromatography, using suitable absorbents andeluents. Among absorbents, there may be mentioned silica gel, cellulose, magnesium silicate, activated aluminum oxide and resins (e.g., Amberlite and Dowex ion exchange resins). Among suitable chromatography solvents, these may be mentioned acetone,dichloromethane, ethyl acetate, 2-ethoxyethyl ether, ethanol, hexanes, and heptane. Particularly suitable absorbent and solvent for the separation of the diastereomeric acylates are silica gel and ethyl acetate/heptane in a flash chromatographicapparatus.
The hydrolysis of an enantiomer 66b to a hydroxyoxazolidine 67 is achieved by means of an alkali metal carbonate (e.g. lithium, potassium, or sodium carbonate) in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol) atabout ambient temperature; reduced temperatures in the range of about 0.degree. C. to about ambient temperature and elevated temperatures in the range of about ambient temperature to about 50.degree. C. may be employed to effect the hydrolysis.
The hydrolysis of a hydroxyoxazolidine 67 to an N-acyloxydiol 68 is preformed in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol) in the presence of an organic acid (e.g., sulfonic acids, such as methanesulfonicacid, benzenesulfonic acid, or 4-methylbenzenesulfonic acid, or a carboxylic acid, such as trifluoroacetic acid). Sulfonic acids are preferred; 4-methylbenzenesulfonic acid is most preferred. Methanol is also preferred. The hydrolysis of occursreadily at ambient temperature. Reduced temperatures in the range of about 0.degree. C. to ambient temperature and elevated temperatures in the range of about ambient temperature to about 50.degree. C. may be employed, however.
The hydrolysis of an N-acyloxydiol 68 to a 2-aminopropan-1,3-diol 69 is achieved by means of a mineral acid in an alkanol, or mixtures thereof. Included among mineral acids are hydrochloric, hydrobromic, and hydroiodic acids. Hydrochloric acidis preferred. Included among alkanols are methanol, ethanol, 1- and 2-propanol, and 1,1-dimethylethanol. Mixtures of methanol and ethanol are preferred. While the hydrolysis temperature is not narrowly critical, it is convenient to carry out thehydrolysis at ambient temperature.
The enantiomers of the 2-amino-1,2-propanediols of the present invention, and derivatives thereof, are also prepared by condensing a carboxaldehyde 72 with, for example, a chiral haloacetyl-4-phenylmethyloxazolidinone 77a ##STR55## wherein Hal ischloro, bromo, or iodo, and W is as hereinbeforedescribed, having the S-configuration at the 4-position, the preparation of which is described in D. A. Evans and A. E. Weber, Journal of the American Chemical Society, 109, 7151 (1981), to provide anoxazolidinylhalohydrin 73, which is converted to an azidohydroxyoxazolidine 74, cleaved to an azidohydroxypropionate 75, and reduced to an aminodiol 76. The condensation is effected by treating an aldehyde 72 with a haloacetyloxazolidinone 73 in thepresence of a condensing agent, for example, a dialkyl borontriflate 78
wherein R.sup.34 is alkyl, such as di-n-butyl borontriflate and an acid acceptor, for example, a trialkylamine such as triethylamine or 4-dimethylaminopyridine, triethylamine being preferred, in ethereal solvent. Among ethereal solvents, theremay be mentioned diethyl ether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, and tetrahydrofuran. Diethyl is preferred. The condensation is generally carried out at a reduced temperature within the range of about -25.degree. to about100.degree. C., a condensation temperature of about -78.degree. C. being preferred.
The conversion of a halohydrin 73 to an azidohydrin 74 is accomplished by treating a halo derivative 73 with an alkali metal azide, e.g., lithium, sodium or potassium azide, sodium azide being preferred, in a dipolar aprotic solvent, e.g.,dimethylacetamide, dimethylformamide, hexamethylphosphoramide, N-methylpyrrolidione, or dimethylsulfoxide, dimethylsulfoxide being preferred, at about ambient temperature, although reduced temperatures (about 0.degree. C. to about ambient temperature)or elevated temperatures (about ambient temperature to about 50.degree. C.) may be employed.
The cleavage of a 4(S)-phenylmethyloxazolidinone 74 to an ester 75 is achieved by treating an oxazolidinone 74 with an alkoxymagnesium halide, for example, methoxymagnesium bromide, prepared in situ from an alkylmagnesium halide, for example,methylmagnesium bromine, and an alkanol, for example, methanol in an alkanol/halocarbon solvent, for example methanol/dichloromethane at about 0.degree. C. Elevated temperatures up to about 50.degree. C. may be employed to effect the cleavage.
The reduction of an azidoester 75 to an enantiomeric 2-amino-1,3-propanediol 76 having the S-absolute configuration is realized by treating an azidoester 75 with an alkali metal hydride, for example, lithium aluminum hydride (although sodium orpotassium alumina hydride may be used), in diethyl ether (although other ethereal solvents such as 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran or dioxane may also be used). The reduction of both the azido and ester groups proceedssmoothly at about 0.degree. C. Elevated temperatures dependent upon the boiling point of the solvent system may also be employed.
A 2-aminopropane-1,3-diol 82, having the R-absolute configuration, is prepared by the aforementioned processes starting from carboxaldehyde 72 and haloacetyl-4-phenylmethyloxazolidinone 77b ##STR56## wherein Hal is as hereinbeforementioned and Wis as hereinbeforedescried, having the R-configuration at the 4-position.
Alternatively, an enantiomeric 2-aminopropane-1,3-diol of the present invention is prepared by reducing a trans-propenoate 83, prepared from an appropriate aldehyde and a (carbalkoxymethylene)triphenylphosphorane in a conventional Wittigreaction, is reduced to a carbinol 84 and epoxidized under asymmetric conditions to an epoxycarbinol 85, which in turn, is condensed with a benzoylisocyanate to provide a benzoylcarbamate, 86 cyclized to an oxazolidinone 87, and cleaved to anaminopropanediol 88.
The reduction is achieved by treating an alkyl propenoate 83 with an aluminum hydride such as, for example, diisobutylaluminium hydride in an ethereal solvent such as, for example, tetrahydrofuran, at a reduced temperature of about -78.degree. C. to provide a carbinol 84.
The asymmetrically induced expoxidation of a trans-alkyl propenate 84 to a 2S-trans-oxirane 85 is accomplished by means of a reaction system containing a base, an epoxidizing agent, and a chiral reagent in a suitable solvent. Among bases, theremay be mentioned alkoxides such as alkali metal alkoxides, alkaline earth alkoxides, and transition metal alkoxides. Examples of alkali metal alkoxides include lithium, sodium, and potassium alkoxides. Examples of alkaline earth alkoxides includemagnesium and calcium alkoxides. Examples of transition alkoxides include titanium, nickel, zinc alkoxides. Examples of alkoxy groups include methoxide, ethoxide, 1- and 2-propoxide, and 2,2-dimethylethoxide. Transition metal alkoxides are preferred;titanium (IV) 2-propoxide is most preferred.
A variety of epoxidizing agents may be used in this enantioselective synthesis. Among these are organic peracids, for example, perbenzoic acid, peracetic acid, performic acid, and monoperththalic acid, hydrogen peroxide and alkylhydroperoxidesderivatives thereof such as tert-butylhydroxyperoxide, the preferred reagent.
The key reagent in this heterogeneous asymmetric epoxidation, the chiral reagent, may be selected from a wide group of optically active organic acids and ester or amide derivatives thereof. Included within this group are tartaric acid anddialkyltartrates, and camphoric acid and dialkyl camphorates. Optically active dialkyltartrates are preferred; di-2-propyltartrate is most preferred. When (+)-di-2-propyltartrate is used, a 2S-trans-oxirane 85 is formed selectively.
Suitable solvents for the expoxidation include halocarbons such as for example dichloromethane, 1,1- and 1,2-dichloroethane and ethylene dichloride. Dichloromethane is preferred.
The epoxidation is generally conducted at a reduced temperature of about -78.degree. to about a reaction temperature of about -20.degree. C. being preferred.
The condensation of an optically active hydroxyoxirane 85 with a benzoylisocyanote 89 ##STR57## wherein W is as hereinbeforedefined is conveniently carried out in a halocarbon solvent of the type mentioned immediately above, generally indichloromethane at about ambient temperature, which temperature is not narrowly critical.
The cyclization of a carbamate 86 to a hydroxyoxazolidinone 87 is effected by an alkali metal hydride selected from the group comprising lithium, sodium, or potassium hydride in a ethereal solvent selected from the group comprising diethyl ether,2-methoxyethyl ether, 1,2-dimethoxyether, tetrahydrofuran, or dioxane. Sodium hydride suspended in tetrahydrofuran is preferred, as is a cyclization temperature of about the reflux temperature of the reaction medium, although the reaction proceedsreadily at reduced temperatures to about ambient temperature.
The hydrolysis of hydroxyoxazolidinone 87 to aminopropanediol 88 is achieved in an alkanol solvent, e.g., methanol, ethanol, 1-, 2-propanol or 2,2-dimethylethanol, by means of a base such as aqueous alkali metal hydroxide, e.g., sodium orpotassium hydroxide, about ambient temperature. Ethanol and aqueous sodium hydroxide are the preferred solvent and base.
By applying the aforedescribed process depicted in Reaction Scheme M and employing the antipode of the chiral reagent, e.g., (-)-diethyltartrate in the preferred synthesis, 2-amino-1,3-propanediol 93 is obtained via hydroxy oxirane 90,benzoylcarbamate 91, hydroxyoxazolidinone 92
A 1-alkenyl-2-amino-1,3-propanediol, e.g., a 1-alkenylpyridinyl-2-amino-1,3-propanediol 17, is prepared by reduction of a 1-alkynylpyridinyl-2-acylamino-1,3-propanediol 6 via a 1-alkenylpyridinyl-2-acylamino-1,3-propanediol 16. See ReactionScheme C. Alternatively, a 1-alkenyl-2-amino-1,3-propanediol, e.g., a 1-alkenylthienyl-2-amino-1,3-propanediol 27, is prepared by condensation of a halothiophenecarboxyaldehyde 25 wherein X is bromo with a tri-n-butyl-1-alkenylstannane 24 in the presenceof 2,6-di-t-butyl-4-methylphenol and tetrakis(triphenylphosphine)palladium(O) in an aromatic solvent such as toluene at room temperature to a 1-alkenylthiophenecarboxaldehyde 26 (see Reaction Scheme D), which, in turn, is converted to a 2-amino-1,3-diol27 and derivatives thereof by the processes outlined in Reaction Schemes A, B, and C.
The requisite tri-n-butyl-l-alkenylstannane 24 is prepared by reductive condensation of an alkyne 28 with tri-t-butylhydride in the presence of azobisisobutyronitrile.
To synthesize a 2-amino-1-propanol 98 of the present invention, an aldehyde 94 is reduced to a methanol 95 wherein R.sup.38 is hydrogen by conventional methods, which is converted to an amidomalonate 96 wherein R.sup.5 and X are ashereinbeforedescribed and R.sup.37 is alkyl via a sulfonate 95 wherein R.sup.38 is SO.sub.2 R.sup.39 wherein R.sup.39 is alkyl and, in turn, reduced to a hydroxyamide 97 and hydrolyzed to an aminocarbinol 98. The conversion is carried out by treating amethanol 95 (R.sup.38 is hydrogen) with an alkylsulfonyl halide 99a
wherein R.sup.39 is alkyl and Hal is chloro or bromo in a halocarbon solvent, e.g., dichloromethane, trichloromethane, 1,1- and 1,2-dichloroethane, dichloromethane being preferred, in the presence of an acid acceptor, e.g., a tertiary amine suchas triethylamine, pyridine, and 4-dimethylpyridine, triethylamine being preferred, at about ambient temperature to provide a sulfonate 95 (R.sup.38 is SO.sub.2 R.sup.39). Optionally, without isolation, the sulfonate 95 is then treated with anamidomalonate 100 ##STR58## wherein R.sup.38 is alkyl in an alkanol in the presence of a corresponding alkali metal alkoxide. Included among alkanols and corresponding alkali metal alkoxides are methanol and lithium, sodium, and potassium methoxide,ethanol and lithium, sodium, and potassium ethoxide, 1- and 2-propanol and lithium, sodium, and potassium 1- and 2-propoxide, and 1,1-dimethyl ethanol and lithium, sodium, and potassium 1,1-dimethylethoxide. Sodium ethoxide in ethanol is preferred. This step of the conversion proceeds readily at about ambient temperature.
The reduction of a malonate 96 to an amido alcohol 97 is performed by treating the former with an alkali metal borohydride such as, for example, sodium or lithium borohydride, lithium borohydride being preferred, in an ethereal solvent such as,for example, diethylether, 2-methoxyethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, and dioxane, tetrahydrofuran being preferred, at a reduction temperature within a range compatible with the reaction medium. When tetrahydrofuran is used as thesolvent, a reaction temperature within the range of about 40.degree. to about 80.degree. C. is preferred, a reaction temperature of about 60.degree. C. is most preferred.
The hydrolysis of an amide 97 to an amino alcohol 98 is achieved by treating an amide 97 with an alkali metal hydroxide, for example, lithium, sodium, or potassium hydroxide, sodium hydroxide being preferred in alkanol, for example, methanol,ethanol, 1- or 2-propanol, or 1,1-dimethylethanol, ethanol being preferred, at a hydrolysis temperature of about 65.degree. C., when ethanol is used as the solvent.
To gain entry into the indole series, i.e., to prepare a 2-amino-1,3-propanediol 104 characterized by the presence of an indole moiety, the nitrogen of an indole carboxaldehyde 101 is protected by, for example, a sulfonyl function to provide aprotected indolecarboxaldehyde 102, which may be converted to an indolyaminopropanediol 104 by the processes described herein and conventional methods. To protect the indole function prior to subsequent transformations, an indole carboxaldehyde 101wherein X is bromo is treated with a sulfonyl halide 99b ##STR59## wherein W is a hereinbeforedescribed and Hal is bromo or chloro in an ethereal solvent, for example, tetrahydrofuran in the presence of an acid acceptor, for example, triethylamine at areaction temperature about 65.degree. C. Other ethereal solvents and acid acceptors may be employed, however. Among them may be mentioned dioxane, 1,2-dimethoxyethane and 2-methoxyethyl ether, and pyridine and 2-dimethylaminopyridine, respectively. Other reaction temperatures, among them temperatures in the range of about 50.degree. to 80.degree. C., may also be employed.
To fabricate a 2-amino-1,3-propanediol having an alkanoylaryl substituent at the 3-position of the aminodioic side-chain, i.e., to prepare, for example, an alkanoylphenylaminopropanediol 106 wherein R.sup.5' is alkyl,alkynylphenylaminopropanediol is hydrolyzed in an ethereal solvent, for example, tetrahydrofuran in the presence of mercuric oxide and a mineral acid, for example, sulfuric acid at a preferred reaction temperature of about room temperature.
To construct a 2-aminopropane-1,3-diol having an alkoxyaryl moiety at the 3-position of the aminodiol side-chain, i.e., to prepare, for example, alkoxy phenylaminopropanediol 111 wherein R.sup.5 is as hereinbeforedescribed, an alkanoyloxybenzaldehyde 107 wherein R.sup.41 ia alkyl is converted to an amidoester 108 wherein R.sup.11, R.sup.12, and R.sup.41 are as hereinbeforedescribed by processes also hereinbeforedescribed, which is reduced to hydroxyphenyldiol 109 wherein R.sup.12 is ashereinbeforedescribed and, in turn, alkylated to alkoxyphenyldiol 110 and hydrolyzed by processes hereinbeforedescribed to alkoxyphenylaminopropanediol 111. The reduction of an alkanoylphenylpropionate 108 is achieved by treating a propionate 108 with aalkali metal borohydride, e.g., lithium borohydride, in ethereal solvent, for example, tetrahydrofuran at a reduced temperature of about 0.degree. C. The alkylation is performed by treating a phenol 109 with an alkyl halide 112
wherein R.sup.5 is as hereinbeforedescribed and Hal is bromo, chloro, or iodo in a dipolar aprotic solvent, e.g., dimethylacetamide, dimethylformamide, hexamethylphosphoramide, or dimethylsulfoxide, dimethylformamide being preferred, in thepresence of an alkali metal carbonate, including lithium, sodium, potassium, and cesium carbonate, and cesium carbonate being preferred. The alkylation is preferrably carried out at about room temperature. Reduced temperatures within the range of about0.degree. C. to about room temperature and elevated temperatures form about room temperature to about 100.degree. C. may be employed to effect the alkylation.
By employing the appropriate starting materials and the processes described herein, additional 2-amino-1,3-propanediols of the present invention may be fabricated. For instance, starting from available substituted naphthalenes,naphthylaminopropanediols 112 ##STR60## wherein R.sup.5 and X are as hereinbeforedescribed may be constructed.
The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are useful as agents for the relief of memory dysfunction, particularly dysfunctions associated with decreased cholinergic activity such as those foundin Alzheimer's disease. Relief of memory dysfunction activity of the instant compounds is demonstrated in the dark avoidance assay, an assay for the determination of the reversal of the effects of scopolamine induced memory deficits associated withdecreased levels of acetylcholine in the brain. In this assay, three groups of 15 male CFW mice were used--a vehicle/vehicle control group, a scopolamine/vehicle group, and a scopolamine/drug group. Thirty minutes prior to training, the vehicle/vehiclecontrol group received normal saline subcutaneously, and the scopolamine/vehicle and scopolamine/drug groups received scopolamine subcutaneously (3.0 mg/kg, administered as scopolamine hydrobromide). Five minutes prior to training, the vehicle/vehiclecontrol and scopolamine/vehicle groups received distilled water and the scopolamine/drug group received the test compound in distilled water.
The training/testing apparatus consisted of a plexiglass box approximately 48 cm long, 30 cm high and tapering from 26 cm wide at the top to 3 cm wide at the bottom. The interior of the box was divided equally by a vertical barrier into a lightcompartment (illuminated by a 25-watt reflector lamp suspended 30 cm from the floor) and a dark compartment (covered). There was a hole at the bottom of the barrier 2.5 cm wide and 6 cm tall and a trap door which could be dropped to prevent an animalfrom passing between the two compartments. A Coulbourn Instruments small animal shocker was attached to two metal plates which ran the entire length of the apparatus, and a photocell was placed in the dark compartment 7.5 cm from the vertical barrierand 2 cm off the floor. The behavioral session was controlled by PDP 11/34 minicomputer.
At the end of the pretreatment interval, an animal was placed in the light chamber directly under the light fixture, facing away from the door to the dark chamber. The apparatus was then covered and the system activated. If the mouse passedthrough the barrier to the dark compartment and broke the photocell beam within 180 seconds, the trap door dropped to block escape to the light compartment and an electric shock was administered at an intensity of 0.4 milliamps for three seconds. Theanimal was then immediately removed front the dark compartment and placed in its home cage. If the animal failed to break the photocell beam within 180 seconds, it was discarded. The latency is seconds for each mouse was recorded.
Twenty-four hours later, the animals were again tested in the same apparatus except that no injections were made and the mice did not receive a shock. The test day latency in seconds for each animal was recorded and the animals were thendiscarded.
The high degree of variability (due to season of the year, housing conditions, and handling) found in one trial passive avoidance paradigm is well known. To control for this fact, individual cutoff (CO) values were determined for each test,compensating for interest variability. Additionally, it was found that 5 to 7% of the mice in the scopolamine/vehicle control groups were insensitive to scopolamine at 3 mg/kg, sc. Thus, the CO value was defined as the second highest latency time inthe control group to more accurately reflect the 1/15 expected control responders in each test group. Experiments with a variety of standards repeated under a number of environmental conditions led to the development of the following empirical criteria:for a valid test, the CO value had to be less than 120 sec and the vehicle/vehicle control group had to have at least 5/15 animals with latencies greater than CO. For a compound to be considered active the scopolamine/compound group had to have at least3/15 mice with latencies greater than CO.
The results of the dark avoidance test are expressed as the number of animals per group (%) in which this scopolamine induced memory deficit is blocked as measured by an increase in the latency period. Relief of memory dysfunction activity forrepresentative compounds of the present invention is presented in Table 1.
TABLE 1 ______________________________________ Dose Percent of Animals with (mg/ Scopolamine Induced Compound kg, sc) Memory Deficit Reversal ______________________________________ ethyl erythro-2-acetamido- 3.0 27 3-[6-(1-decynyl)-2-pyridinyl]- 3-hydroxypropionate erythro-N-{1-[6-(1-decynyl)- 3.0 33 2-pyridinyl]-1,3-dihydroxy- 2-propanyl}acetamide physostigmine 0.31 20 ______________________________________
Scopolamine induced memory deficit reversal is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediol, and related compounds are administered to a subject requiring such treatment as an effective oral,parenteral or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens shouldbe adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only andthat they do not, to any extent, limit the scope or practice of the invention.
The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are also useful as antiiflammatory agents due to their ability to reduce inflammation in mammals. The antiinflammatory activity is demonstrated in theTPA-induced ear edema assay and the arachidonic acid-induced ear edema test (see J. M. Young, et at., Journal Investigative Dermatology, 80, 48 (1983)).
In the TPA-induced ear edema assay, TPA (12-O-tetradecanoylphorbol-13-acetate) was dissolved in 30/70 propylene glycol/ethanol and was applied to the right ear of groups of 6 female Swiss Webster mice, which were housed together in a cage understandard conditions for 1 week prior to use with food and water ad lib, at a volume of 20 .mu.l so that a total of 10 .mu.g of TPA is delivered to the inner and outer surfaces of the ear. The test compound was dissolved in the vehicle and was applied tothe right ear (the inner and outer surface) at a volume of 20 .mu.l so that a total of 10 .mu.g of the compound was delivered to the ear. After about 5 hours, the animals were sacrificed, a 4 mm diameter plug was taken from each ear and weighed. Thedifference between the right and left ear plug weights for each animal was determined. The antiinflammatory activity of the test compound is expressed as the mean percent change in the ear plug weight of the treated animals compared to the mean percentchange in the plug weight of the control animals. Antiinflammatory activity of representative compounds of the instant invention as determined in this assay are presented below in Table 2.
TABLE 2 ______________________________________ Antiinflammatory Activity Percent Decrease in Ear Plug Compound Weight at 10 .mu.g/ear ______________________________________ erythro-2-amino-1- 66 (6-decyl-2-pyridinyl)- 1,3-dihydroxypropane ethyl erythro-2-acetamido-3- 50 [6-(1-dodecynyl)- 2-pyridinyl]-3-hydroxypropionate erythro-N-{1-[6-(1-dodecynyl)- 59 2-pyridinyl]-1,3-dihydroxy- 2-propanyl}acetamide erythro-2-amino-1-(6-dodecyl- 24 2-pyridinyl)-1,3-propanediol threo-2-amino-1-(6-decyl)- 30 2-pyridinyl)-1,3-propanediol D-erythro-sphingosine 46 ______________________________________
In the arachidonic acid-induced ear edema assay, the test compound was dissolved in 30/70 propylene glycol/ethanol and was applied to both ears of groups of 6 female Swiss Webster mice, which were housed together in a cage under standardconditions for 1 week prior to use with food and water ad lib, at a volume of 20 .mu.l so that a total of 1.0 mg of test compound was delivered to each ear over the inner and outer surfaces. The same volume (20 .mu.l) of vehicle was applied to each earof a control group of mice. After 30 minutes, arachidonic acid was applied to the right ear of each mouse of each group in the amount of 4 mg/ear. Vehicle was applied to the left ear of each mouse of each group at a volume of 20 .mu.l/ear. After anadditional hour, the mice were sacrificed and a 4 mm plug was taken from each ear and weighed. The difference between the right and left ear plugs was determined for each animal. The antiinflammatory activity of the test compound is expressed as themean percent change in the ear plug weight of the treated animals relative to the mean percent change in weights of control animals' ear. Antiinflammatory activity of representative compounds of the present invention as determined in this assay arepresented below in Table 3.
TABLE 3 ______________________________________ Antiinflammatory Activity Percent Decrease in Ear Plug Compound Weight at 1 mg/ear ______________________________________ erythro-2-amino-1- 32 (6-decyl-2-pyridinyl)- 1,3-dihydroxypropane D-erythro-sphingosine +9 ______________________________________
Inflammation reduction is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols are administered topically, including ophthalmic administration, to a subject requiring such treatment as an effective topicaldose of from 0.001 to100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood however, that for any particular subject, specific dosage regimens should be adjusted according tothe individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to anyextent, limit the scope or practice of the invention.
The 1-alkyl-, 1-alkenyl-, and 1-alkynyl-2-amino-1,3-propanediols of the present invention are also useful as inhibitors of tumor or neoplastic cell growth by virtue of their ability to reduce cell proliferation as demonstrated in the proteinkinase C assay. (see U. Kikkawa, et al., Biochemical and Biophysical Research Communications, 135, 636 (1986) and R. M. Bell, et al. "Methods in Enzymology, Hormone Action," Part J, P. M. Conn, Ed., Academic Press, Inc., New York, N.Y. 1986, page 353).
Protein kinase C enzyme extract was prepared from the brain of male Wistar rats weighing 180 to 200 g and purified by the method of U. Kikkawa, et al., ibid. 636. The purified extract was stored at -80.degree. C., and aliquots were used in theprotein kinase C assay performed by a modification of the method of R. M. Bell, et al., ibid. al 354.
To perform the assay, duplicate aliquots of duplicate samples are employed. Basal or unstimulated protein kinase C, phosphatidylserine/diacylglycerol stimulated protein kinase C, and test samples are run in each assay. Protein kinase C extract(1-5 .mu.g of protein; 10 .mu.l); an 8 .mu.l solution of N-2-hydroxyethylpiperazine-N'-2-ethylsulfonic acid (500 mM), magnesium chloride (40 mM), and ethylenediaminoetetraacetic acid (10 mM); dithiothreitol (20 mM; 8 .mu.l), Type III histone (12 .mu.g; 8.mu.l), and calcium chloride (11 mM; 8 .mu.l) was added to each unstimulated protein kinase C sample assay tube, chilled in ice. Phosphatidylserine/diacylglycerol (4 .mu.g; 8 .mu.l) was added to each stimulated protein kinase sample assay tube, chilledin ice. The test compound (10.sup.-4 to 10.sup.-12 M in 4 .mu.l dimethylsulfoxide) was added to the test sample tubes, chilled in ice. The volume for all sample tubes was brought to 72 .mu.l with distilled water (18 .mu.l for stimulated samples; 26.mu.l for unstimulated samples without 8 .mu.l of phosphatidylserine/diacylglycerol). The assay tubes were allowed to warm to 25.degree. C. and an 8 .mu.l mixture of adenosine 5'-triphosphate (100 .mu.M) and .sup.32 P-adenosine triphosphate (1 to2.times.10.sup.5 counts per minute) was added to each tube for a final volume of 80 .mu.l per tube. After 2 min, the reaction (the incorporation of phosphorous into Type III histone) was terminated by spotting the assay mixture on phosphocellulosepaper. The spots are cut out of the paper and the radioactivity (counts per min) of each spot was determined in a scintillation counter. Percent protein kinase C inhibitory activity, i.e., the percent inhibition of the incorporation of .sup.32phosphorous from .sup.32 P-adenosine triphosphate into Type III histone, is calculated as follows: ##EQU1##
Protein kinase C inhibitory activity of representative compounds of the present invention expressed as the calculated concentration of test compound effecting a 50% inhibition of phosphorous uptake (IC.sub.50) is presented below in Table 4.
TABLE 4 ______________________________________ Protein Kinase Inhibitory Activity Compound IC.sub.50 (.mu.M) ______________________________________ ethyl erythro-2-acetamido- 29 3-[6-(1-dodecynyl)-2- pyridinyl]-3-hydroxypropionate cis-erythro-N-{1-[6-(1-dodecenyl)- 66% @ 100 .mu.M 2-pyridinyl]-1,3-dihydroxy-2- propanyl}-acetamide erythro-2-amino-1-(6-dodecyl-2- 8.5 pyridinyl)-1,3-propanediol erythro-2-amino-1-(6-decyl-2- 48 pyridinyl)-1,3-dihydroxypropane threo-2-amino-1-(6-decyl-2- 25 pyridinyl)-1,3-dihydroxypropane D-erythro-sphingosine 6.7 ______________________________________
Protein kinase C inhibition is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, and related compounds are administered to a subject requiring such treatment as an effective oral, parenteral, intravenous,or topical dose of from 0.001 or 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should beadjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of the invention.
The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols of the present invention are also useful as antibacterial and antifungal agents due to their ability to inhibit bacterial and fungal growth in mammals. Antibacterial andantifungal activity are demonstrated in conventional antimicrobial assays assays (see D. J. Bibel, et al., The Journal of Investigative Dermatology, 92, 632 (1989).
In the aerobic antibacterial assay, the sensitivity of aerobic bacteria was tested by means of the agar dilution test in Mueller-Hinton agar. Plates were inoculated with a multipoint inoculator which delivered 5.times.10.sup.4 CFU/spot ofstationary, freshing diluted cultures of the strains concerned. The minimum inhibitory concentration (MIC) was taken as the lowest concentration at which no visible growth could be detected after 24 hours at 37.degree. C.
In the anerobic assay, the susceptibility of obligate gram-positive and gram-negative anaerobes was tested using the agar dilution test on Wilkins-Chalgren agar. Overnight cultures of the appropriate test strains diluted 1:10 in freshthioglycollate medium were used as the inoculum. The MICs of the antibiotics were determined after the plates had been incubated in anaerobic jars for 48 hours at 37.degree. C.
Antibacterial activity of representative compounds of the instant invention as determined in this assay is presented below in Tables 5 and 6.
TABLE 5 ______________________________________ Antibacterial activity (MIC, mg/l) erythro-2-amino-1-(6- decyl-2-pyridinyl)- D-erythro- Aerobic Bacteria Strain 1,3-dihydroxypropane sphingosine ______________________________________Staph. aureus SG511 12.50 25.0 285 12.50 25.0 503 6.25 25.0 Strept. pyogenes 308 A 6.25 12.5 77 A 6.25 25.0 Strept. faecium D 12.50 25.0 E. coli O 78 12.50 >100.0 TEM 25.00 >100.0 1507E 12.50 >100.0 DC0 12.50 >100.0 DC2 6.25 25.0 S. typhimurium 12.50 >100.0 Klebsiella spp. 1082E 12.50 25.0 1522E 12.50 >100.0 E. cloacae P99 12.50 >100.0 1321E 12.50 50.0 ______________________________________
TABLE 6 __________________________________________________________________________ Antibacterial activity (MIC, mg/l) Erythro-2-amino- Erythro-N{1-[6-(1-dodecynyl)- Erythro-2-amino- Anerobic Bacteria 1-(6-decyl-2-pyridinyl)- 2-pyridinyl]-1,3-dihydroxy- 1-[5-(1-dodecynyl)- D-erythro- Strain 1,3-dihydoxypropane 2-propanyl}acetamide 2-thienyl]-1,3-propanediol sphingosine __________________________________________________________________________ Bact. fragilis 312 12.503.13 6.25 25.0 960 6.25 3.13 6.25 12.5 1313 12.50 6.25 6.25 25.0 17390 12.50 6.25 3.13 25.0 18125 12.50 3.13 3.13 25.0 19016 12.50 6.25 6.25 25.0 Bact. ovatus 103 6.25 3.13 3.13 12.5 Bact. vulgatus 1446 12.50 3.13 3.13 25.0 Bact.thetaiotaom. 123 6.26 3.13 3.13 25.0 1428 12.50 6.25 6.25 25.0 1445 12.50 6.25 3.13 25.0 Bact. distasonis 1366 12.50 6.25 3.13 12.5 Fusobact. varium 5262 12.50 6.25 3.13 25.0 3085 12.50 6.25 6.25 25.0 Spaeroph. freundii 1369 12.50 3.13 1.56 Peptostr. anaerobius 932 12.50 6.25 6.25 12.5 Propionibact. acnes 6919 12.50 6.25 3.13 12.5 6922 12.50 6.25 1.56 12.5 Clost. tetani 19406 12.60 12.50 6.25 50.0 Clost. perfringens 194 12.60 12.00 6.25 6.25 __________________________________________________________________________
In the antifungal assay, utilizing a microtitration technique (U-shaped, 96 well-plate), the test compound (10 mg) is dissolved in a suitable solvent (10 ml dist. water, or 1 ml org. solvent+9 ml dist. water).
The microtiter plate is prepared as follows: The wells are each filled (2 rows/strain) with 50 .mu.l neopeptone-dextrose broth (12-channel pipette). In addition, one row/strain is coated with 50 .mu.l yeast-nitrogen base/well for yeasts andmoulds. Subsequently, 50 .mu.l compound solution are added to each well in the first row, mixed and diluted further by transferral of 50 .mu.l respectively in the ratio 1:2. All wells are then inoculated with 150 .mu.l standardized organism suspension(yeasts: 1.times.10.sup.3 organisms/ml suspension; cutaneous fungi and moulds: 1.6.times.10.sup.5 organisms/ml suspension); the total volume is 200 .mu.l per well.
There is also a growth control (inoculated, not medicated), a solvent control (inoculated, not medicated, containing solvent as in medicated rows) and a negative control (not inoculated, not medicated).
Incubation for 5 days at 30.degree. C. is followed by photometric evaluation. The obtained measurements are checked visually (macroscopically and microscopically) and corrected where necessary.
Criteria for Evaluation of the Antimycotic Effect
a. Photometric measurements (matrix method)
b. Growth, macroscopic evaluation
c. Growth, microscopic evaluation (inversion light microscope, magn. 64.times.).
Antifungal activity of representative compounds of the instant invention as determined in the microtiter assay is presented below in Table 7.
TABLE 7 ______________________________________ Antifungal Activity Pathogen Strain MIC [.mu.g/ml] ______________________________________ erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]- 1,3-dihydroxy-2-propanyl}acetamide TrichophytonMentagrophytes 100/25 7.810 Trichophyton Rubrum 101/85 31.250 Microsporum Canis 150/353 0.970 Candida Albicans 200/175 125.000 Aspergillus Niger 500/284 125.000 Trichophyton Vaginalis 111/216 15.625 erythro-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-dihydroxypropane Trichophyton Mentagrophytes 100/25 31.250 Trichophyton Rubrum 101/85 31.250 Microsporum Canis 150/353 31.250 Candida. Albicans 200/175 31.250 Aspergillus Niger 500/284 31.250 Trichophyton Vaginalis 111/216 15.625 erythro-2-Amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol Trichophyton Mentagrophytes 100/25 3.900 Trichophyton Rubrum 101/85 15.625 Microsporum Canis 150/353 3.900 Candida Albicans 200/175 1.950 Aspergillus Niger 500/284 3.900 Trichophyton Vaginalis 111/216 15.625 Cyclopirox Trichophyton Mentagrophytes 100/25 1.950 Trichophyton Rubrum 101/85 1.950 Microsporum Canis 150/353 1.950 Candida Albicans 200/175 1.950 Aspergillus Niger 500/2840.970 Trichophyton Vaginalis 111/216 15.625 Clotrimazol Trichophyton Mentagrophytes 100/25 0.970 Trichophyton Rubrum 101/85 0.240 Microsporum Canis 150/353 0.060 Candida Albicans 200/175 3.900 Aspergillus Niger 500/284 1.950 TrichophytonVaginalis 111/216 62.500 ______________________________________
Bacterial and fungal growth inhibition is achieved when the present 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, and related compounds are administered to a subject requiring such treatment as an effective oral, parenteral,intravenous, or topical, including ophthalimic administration, dose of from 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particularsubject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosagesset for herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
Compounds of the present invention include:
a. erythro-2-amino-1-(5-decyl-2-furyl)-1,3-dihydroxypropane;
b. erythro-2-amino-1-(5-decyl-3-isothiazolyl)-1,3-dihydroxypropane;
c. threo-2-amino-1-[5-decyl-3-(2-oxopyrrolyl)]-1,3-dihydroxypropane;
d. erythro-2-amino-1-[6-decyl-2-(4-methylpyridinyl)]-1,3-dihydroxypropane;
e. threo-2-amino-1-[6-decyl-2-(4-methoxypyridinyl)]-1,3-dihydroxypropane;
f. erythro-2-amino-1-[6-decyl-2-(5-chloropyridinyl)]-1,3-dihydroxypropane;
g. threo-2-amino-1-[6-decyl-2-(4-trifluoromethylpyridinyl)]-1,3-dihydroxyprop ane;
h. erythro-2-amino-1-[6-(5-phenylpentyl-2-pyridinyl)-1,3-dihydroxypropane;
i. erythro-2-amino-1-(2-decyl-4-thiazolyl)-1,3-dihydroxypropane;
j. erythro-2-amino-1-(2-decyl-4-oxazolyl)-1,3-dihydroxypropane;
k. erythro-2-methylamino-1-(5-decyl-2-thienyl)-1,3-dihydroxypropane
l. erythro-2-dimethylamino-1-(3-decyl)phenyl-1,3-dihydroxypropane;
m. erythro-2-(1,1-dimethylethoxy)carbonylamino-1-(2-dodecynyl-6-pyridinyl)-1, 3-dihydroxypropane;
n. erythro-2-amino-1-(3-(1-decenyl)phenyl)-1,3-dihydroxypropane;
o. ethyl erythro-2-methoxycarbonylamino-3-(2-dodecynyl-6-pyridinyl)-3-hydroxypropio nate;
p. erythro-2-amino-1-(3-(1-decynyl)phenyl)-1,3-dihydroxypropane;
q. erythro-2-amino-1-(3-(1-undecynyl)phenyl)-1,3-dihydroxypropane;
r. erythro-2-amino-1-(4-(1-nonyl)-2-thienyl)-1,3-dihydroxypropane;
s. erythro-2-amino-1-(4-(1-dodecynyl)-2-thienyl)-1,3-dihydroxypropane;
t. erythro-2-amino-1-(4-(1-decyl)-2-thienyl)-1,3-dihydroxypropane;
u. erythro-2-amino-1-(5-nonyl-2-thienyl)-1,3-dihydroxypropane;
v. erythro-2-amino-1-(3-dodecyl-5-isoxazolyl)-1,3-dihydroxypropane;
w. erythro-2-amino-1-(3-decyl-5-isoxazolyl)-1,3-dihydroxypropane;
x. erythro-2-amino-1-(6-(1-dodecenyl)-2-pyridinyl)-1,3-dihydroxypropane;
y. erythro-2-amino-1-(3-(6-phenyl-1-hexynyl)phenyl)-1,3-dihydroxypropane; and
z. erythro-2-amino-1-(5-(6-phenylhexyl)-2-thienyl)-1,3-dihydroxypropane.
Effective amounts of the compounds of the present invention may be administered topically to a subject in the form of sterile solutions, suspensions, ointments, creams, aerosols, or salves. The 1-alkyl-, 1-alkenyl, and1-alkynylaryl-2-amino-1,3-propanediols of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid or base addition salts for purposes of stability, convenience orcrystallization, increased solubility and the like.
Preferred pharmaceutically acceptable acid addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, acetic acid, propionicacid and the like, salts of dibasic carboxylic acids such as, for example, maleic acid, fumaric acid and the like, and salts of tribasic carboxylic acids such as, for example, carboxysuccinic acid, citric acid and the like. Preferred pharmaceuticallyacceptable base addition salts include salts of alkali metals, e.g. sodium or potassium, alkaline earth metals, e.g. calcium or magnesium; or complex salts such as ammonium or substituted ammonium salts such as a mono-, di- or trialkylammonium salts or amono, di- or trihydroxyalkylammonium salts.
For the purpose of topical administration, the active compounds of the invention may be incorporated into a solution, suspension, ointment, cream, gel, aerosol, or salve. These preparations should contain at least 0.1% of active compound but maybe varied to be between 0.05 and about 20% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred topically administered preparations should contain between 0.1 and 10% ofactive compound.
The topical compositions may also include the following components: water, fixed oils, polyethylene, glycols, glycerol, petroleum, stearic acid, beeswax, other synthetic solvents or mixtures thereof; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as .alpha.-tocopherol acetate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; emulsifying agents such as polyoxyethylene monooleate and coloring materials andadjuvants such as ferric oxide or talc. The topical preparation can be enclosed in tubes, bottles, or jars made of metal, glass or plastic.
The active compounds of the present invention may also be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oraltherapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5%of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 75% of the weight of the unit. The amount of present compound in such composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 mgs of active compound.
The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginicacid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physicalform of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of the aforesaid compound, but may be variedbetween 0.5 and about 50% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the active compound.
The oral solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterialagents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicitysuch as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
The following Examples are for illustrative purposes only and are not to beconstrued as limiting the invention.
EXAMPLE 1
6-(1-Dodecynyl)-2-pyridinecarboxaldehyde
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II) chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40.degree. C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (II) chloride (0.024 g), copper (I) iodide (0.024 g), and triethylamine (2.12 ml), and1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40.degree. C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40.degree. C. for 24 hrs. The cooled mixture was concentrated, taken up in ethylacetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate was combinedwith material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexanefollowed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Analysis:
Calculated for C.sub.18 H.sub.25 NO: 79.66% C 9.28% H 5.16% N Found: 79.54% C 9.29% H 4.98% N
EXAMPLE 2
erythro-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide
Ethyl erythro-2-acetamido-3-[6-(1-decynyl)-2-pyridinyl]-3-hydroxypropionate (5.71 g) in dry tetrahydrofuran (75 ml) was slowly added to 2.0M lithium borohydride/tetrahydrofuran (7.6 ml) at 0.degree. under nitrogen, and the mixture was stirred atroom temperature overnight. The reaction mixture was chilled, and 1:1 methanol:water (50 ml) was added slowly followed by glacial acetic acid (0.5ml) until pH 6.5 was obtained. The reaction mixture was concentrated, and the residue azeotroped withmethanol (4.times.40 ml). The residue was slurried with 7.5% sodium bicarbonate solution (15 ml) (pH 8.5), extracted into 3:1-trichloromethane:isopropanol and concentrated. The appropriate fractions were collected and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 49:1-ethyl acetate:methanol. The appropriate fractions were collected and concentrated to give 4.74 g (93%) of product, mp 85.degree.-87.degree. C.
Analysis:
Calculated for C.sub.20 H.sub.30 N.sub.2 O.sub.3 : 69.33% C 8.73% H 8.09% N Found: 69.44% C 8.84% H 8.07% N
EXAMPLE 3
erythro-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-diacetyloxy-2-propanyl}acetami de
N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (4.35 g), acetic anhydride (7.45 ml), triethylamine (16 ml), and 4-dimethylaminopyridine (0.24 g) in dry tetrahydrofuran (80 ml) was stirred at room temperature for 3 days. Thereaction mixture was evaporated, and the residue was warmed with methanol for 20 mins, reevaporated, and the residue was azeotroped with toluene. The residue was taken up in trichloromethane, and 7.5% sodium bicarbonate solution was added until pH 8.5was obtained. The mixture was extracted with trichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was combined with the residue (1.0 g) from a reaction, starting with 0.829 g of acetamide,and purified by flash chromatography on silica gel eluting with 1:1-hexane:ethyl acetate. The appropriate fractions were collected and concentrated to yield 1.61 g (25%) of product.
Analysis:
Calculated for C.sub.24 H.sub.34 N.sub.2 O.sub.5 : 66.95% C 7.96% H 6.51% N Found: 66.65% C 8.04% H 6.36% N
EXAMPLE 4
threo-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-diacetyloxy-2-propanyl}acetamide
N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (4.35 g), acetic anhydride (7.45 ml), triethylamine (16 ml), and 4-dimethylaminopyridine (0.24 g) in dry tetrahydrofuran (80 ml) was stirred at room temperature for 3 days. Thereaction mixture was evaporated, and the residue was warmed with methanol for 20 min, reevaporated and azeotroped with toluene. The residue was taken up in trichloromethane, and 7.5% sodium bicarbonate solution was added until pH 8.5 was obtained. Themixture was extracted with trichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was combined with 1.0 g of the residue from another reaction (0.829 g of acetamide), and purified by flash chromatography onsilica gel, eluting with 1:1-hexane:ethyl acetate to yield 1.02 g (15.9%) of product, mp 59.degree.-61.degree. C.
Analysis:
Calculated for C.sub.24 H.sub.34 N.sub.2 O.sub.5 : 66.95% C 7.96% H 6.51% N Found: 67.21% C 7.83% H 5.92% N
EXAMPLE 5
Ethyl erythro-2-acetamido-3-[6-(1-decynyl)-2-pyridinyl]-3-hydroxypropionate
A 2:1-erythro:threo mixture of ethyl 2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (10.0 g), 1-decyne (5.01 g), bis(triphenylphosphine)palladium chloride (0.42 g) and cuprous iodide (0.06 g) in triethylamine (50 ml) was heated at50.degree.-60.degree. C. for 2.5 hrs. under nitrogen, and then at room temperature overnight. The reaction mixture was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic extract was purified by flashchromatography on silica gel, eluting with 1:1 hexane:ethyl acetate and collecting the appropriate fractions. The appropriate fractions were evaporated. Recrystallization of the residue from ethyl acetate gave 7.8 g (66%) of the product, mp97.degree.-99.degree. C.
Analysis:
Calculated for C.sub.22 H.sub.32 N.sub.2 O.sub.4 : 68.01% C 8.30% H 7.21% N Found: 68.23% C 8.28% H 7.22% N
EXAMPLE 6
Ethyl threo-2-acetamido-3-[6-(1-decynyl-2-pyridinyl]-3-hydroxypropionate
A mixture of ethyl 2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (17.3 g, 97% erythro), 1-decyne (8.67 g), bis(triphenylphosphine)palladium chloride (0.73 g), cuprous iodide (0.10 g), and triethylamine (13.2 g) in tetrahydrofuran (90ml) was heated overnight at 50.degree.-55.degree. C., under nitrogen. The reaction mixture was evaporated, water was added, and the mixture was extracted with ethyl acetate, and concentrated. The residue was purified by flash chromatography on silicagel, eluting with 1:1-hexane:ethyl acetate. The appropriate fractions were collected and evaporated. Recrystallization of the residue from 1:2-hexane:ethyl acetate gave 14.7 g of 19:1-mixture erythro:threo-compounds, and from the mother liquors, 4.66 gof an 8:3 of mixture erythro:threo compounds. Flash chromatography of 2.63 g of the threo-enriched material on silica gel, eluting with 1:1-hexane:ethyl acetate, yielded 0.39 g (3.4%) of product, mp 97.degree.-99.5.degree. C.
Analysis:
Calculated for C.sub.22 H.sub.32 N.sub.2 O.sub.4 : 68.01% C 8.30% H 7.21% N Found: 67.89% C 8.26% H 7.10% N
EXAMPLE 7
erythro-N-{4-[6-(1-Decynyl)-2-pyridinyl]-2,2-dimethyl-1,3-dioxan-5-yl}aceta mide
N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (6.1 g, 3:1/erythro:threo mixture), p-toluenesulfonic acid (3.7 g), and 2,2-dimethoxypropane (43 ml) in dichloromethane (115 ml) were stirred at room temperature overnight, undernitrogen. The reaction mixture was extracted with 0.5M sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel, eluting with2:1-hexane:ethyl acetate to give 2.4 g (35%) of product, as an oil.
Analysis:
Calculated for C.sub.23 H.sub.34 N.sub.2 O.sub.3 : 71.47% C 8.87% H 7.25% N Found: 71.14% C 9.12% H 7.13% N
EXAMPLE 8
threo-N-{4-[6-(1-Decynyl)-2-pyridinyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetami de
N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (6.1 g, 3:1-erythro:threo mixture), p-toluenesulfonic acid (3.7 g), and 2,2-dimethoxypropane (43 ml) in dichloromethane (115 ml) were stirred at room temperature overnight, undernitrogen. The reaction mixture was washed with 0.5M sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed twice on silica gel, eluting with2:1-hexane:ethyl acetate to 1:1-hexane:ethyl acetate to give 0.76 g (11%) of product, as an oil.
Analysis:
Calculated for C.sub.23 H.sub.34 N.sub.2 O.sub.3 : 71.47% C 8.87% H 7.25% N Found: 71.15% C 8.91% H 7.06% N
EXAMPLE 9
Ethyl erythro-2-acetamido-3-[6-(1-dodecynyl)-2-pyridinyl]-3-hydroxypropionate
A solution of 6-(1-dodecynyl)-2-pyridinecarboxaldehyde (5.51 g), acetamidomalonic acid monoethyl ester (3.78 g), and triethylamine (2.8 ml) in dry tetrahydrofuran (30 ml) was stirred at room temperature overnight, under nitrogen. The reactionmixture was evaporated, and the residue was purified on a silica gel column eluting with 1:1-hexane:ethyl acetate to give 7.46 g (89.6%) of product (10:1-erythro:threo mixture). This product was combined with 7.40 g from a prior reaction run on the samescale, and the combined material was recrystallized from 2:1-ethyl acetate:hexane to give 9.62 g (57.7%) of the analytically pure product, mp 86.degree.-87.5.degree. C.
Analysis:
Calculated for C.sub.24 H.sub.36 N.sub.2 O.sub.4 : 69.20% C 8.71% H 6.72% N Found: 69.40% C 8.72% H 6.68% N
EXAMPLE 10
Ethyl erythro-2-acetamido-3-[6-(1-hexynyl)-2-pyridinyl]-3-hydroxypropionate
An 11:1-erythro:threo mixture of ethyl 2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (24.9 g), 1-hexyne (7.39 g), triethylamine (19.0 g), bis(triphenylphosphine)palladium chloride (1.05 g) and cuprous iodide (0.14 g) in drytetrahydrofuran (100 ml) was heated at 55.degree. C. for 6 hrs, under nitrogen. Additional 1-hexyne (6.2 g), triethylamine (7.6 g), bis(triphenylphosphine)palladium chloride (0.53 g), and cuprous iodide (0.07 g) were added at room temperature and thereaction mixture was heated an additional 5.5 hrs. The mixture was evaporated, water was added, and the mixture was extracted with ethyl acetate. The extract was flash chromatographed (silica gel, 1:1-hexane:ethyl acetate). The appropriate fractionswere collected and evaporated. Recrystallization of the residue from 1:1-hexane:ethyl acetate provided 3.8 g (15%) of product, 87.degree.-88.degree. C.
Analysis:
Calculated for C.sub.18 H.sub.24 N.sub.2 O.sub.4 : 65.04% C 7.28% H 8.43% N Found: 65.19% C 7.31% H 8.37% N
EXAMPLE 11
erythro-N-{1,3-Diacetyloxy-1-[6-(1-hexynyl)-2-pyridinyl]-2-propanyl}acetami de
To ethyl erythro-2-acetamido-3-[6-(1-hexynyl)-2-pyridinyl]-3-hydroxypropionate (16.0 g) in dry tetrahydrofuran (140 ml) was added 2.0M lithium borohydride:tetrahydrofuran (24 ml) at 0.degree. C., with stirring, under nitrogen. After theaddition was complete, the mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was chilled and 1:1-methanol:water (80 ml) was added slowly followed by acetic acid (2.8 ml) until a pH of 6.8 was obtained. Thereaction mixture was stirred for 1 hr and evaporated. The residue was azeotroped several times with methanol. A 7.5% sodium bicarbonate solution was added to the residue until a pH of 8.5 was obtained, and the mixture was extracted with 3:1trichloromethane:isopropanol and concentrated. The residue was flash chromatographed on silica gel eluting with 1% methanol:ethyl acetate to give 13.2 g (94%) of erythro-N-{1-[6-(1-hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamid e.
erythro-N-{1-[6-(1-hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (10.3 g), acetic anhydride (21.8 g), triethylamine (32.4 g), and 4-dimethylaminopyridine (0.44 g) in tetrahydrofuran (150 ml) was stirred at room temperature overnight. The reaction mixture was evaporated, methanol was added to the residue, and the solution was warmed at 50.degree. C. for 15 min. The mixture was evaporated. The residue was dissolved in chloroform, and 7.5% sodium bicarbonate solution was added until apH 8 was obtained. The mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed, eluting with 1:1-hexane:ethyl acetate to yield7.3 (55%) of product, mp 97.degree.-99.degree. C.
Analysis:
Calculated for C.sub.20 H.sub.26 N.sub.2 O.sub.5 : 64.16% C 7.00% H 7.48% N Found: 64.17% C 7.00% H 7.44% N
EXAMPLE 12
erythro-N-{1-[6-(1-Hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide
erythro-N-{1,3-Diacetyloxy-1-[6-(1-hexynyl)-2pyridinyl]-2-propanyl}acetamid e (6.7 g) and potassium carbonate (3.3 g) in methanol (100 ml) was stirred for 40 min. The precipitate was collected, and the filtrate was evaporated. A 7.5% sodiumbicarbonate solution was added to pH 8.5, and the mixture was extracted with 3:1-trichloromethane:2-propanol, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. Recrystallization of the residue from 1:1-hexane:ethylacetate gave 4.6 g (88%) of product, mp 75.degree.-77.degree. C.
Analysis:
Calculated for C.sub.16 H.sub.22 N.sub.2 O.sub.3 : 66.19% C 7.64% H 9.65% N Found: 65.99% C 7.55% H 9.65% N
EXAMPLE 13
Ethyl erythro-2-acetamido-3-hydroxy-3-[6-(1-octynyl)-2-pyridinyl]propionate
A mixture of an 11:1-erythro:threo mixture of ethyl 2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (24.9 g), 1-octyne (9.9 g), triethylamine (19.0 g), bis(triphenylphosphine)palladium chloride (1.05 g) and cuprous iodide (0.14 g) in drytetrahydrofuran (100 ml) was heated at 55.degree. C. for 6 hrs, under nitrogen. Additional 1-octyne (4.1 g), triethylamine (3.8 g), bis(triphenylphosphine)palladium chloride (0.53 g), and cuprous iodide (0.07 g) were added at room temperature, and thereaction mixture was heated an additional 4 hrs. The mixture was evaporated, water was added, and the mixture was extracted with ethyl acetate. The solution was flash chromatographed on silica gel eluting with 1:1-hexane:ethyl acetate. The fractions,enriched in the erythro isomer, were evaporated and the residue was recrystallized from 1:1-isopropanol:water to give 3.2 g (12%) of product, mp 81.degree.-83.degree. C.
Analysis:
Calculated for C.sub.20 H.sub.28 N.sub.2 O.sub.4 : 66.64% C 7.83% H 7.77% N Found: 66.62% C 7.77% H 7.75% N
EXAMPLE 14
erythro-N-{1,3-Dihydroxy-1-[6-(1-octynyl)-2-pyridinyl]-2-propanyl}acetamide
To ethyl erythro-2-acetamido-3-hydroxy-3-[6-(1-octynyl)-2-pyridinyl]propionate (9.02 g) in dry tetrahydrofuran (80 ml) was added slowly 2.0M lithium borohydride:tetrahydrofuran (12.5 ml) at 0.degree., under nitrogen. The mixture was stirred atroom temperature overnight, chilled, and 1:1-methanol:water was added slowly followed by glacial acetic acid (1.5 ml) in 1:1-methanol:water (15 ml) until pH 6.8 was obtained. The solution was stirred at room temperature for 1.5 hrs, evaporated, and theresidue was azeotroped with methanol (4.times.40 ml). The residue was slurried with 7.5% sodium bicarbonate solution (25 ml) (pH 8.5), saturated sodium chloride solution (25 ml), extracted with 3:1-trichloromethane:2-propanol, and concentrated. Theresidue was flash chromatographed on silica gel, eluting with ethyl acetate:0.5% methanol. The appropriate fractions were collected and evaporated. The residue was recrystallized (3 times) from ethyl acetate to give 1.24 g (15.6%) of product, mp81.degree.-83.degree. C.
Analysis:
Calculated for C.sub.18 H.sub.26 N.sub.2 O.sub.3 : 67.90% C 8.23% H 8.80% N Found: 68.03% C 7.97% H 8.70% N
EXAMPLE 15
Ethyl erythro-2-acetamido-3-[6-(1-hexadecynyl)-2-pyridinyl]-3-hydroxypropionate
A solution of 6-(1-hexadecynyl)-2-pyridinecarboxaldehyde (17.4 g), acetamidomalonic acid monoethyl ester (10.6 g), and triethylamine (5.4 ml) in dry tetrahydrofuran (85 ml) was stirred at room temperature for 3 days, under nitrogen. The reactionmixture was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified ona silica gel column, eluting with 2:1- to 1:1-hexane:ethyl acetate. The appropriate fractions were collected and evaporated. The residue was recrystallized from ethanol and then 85% ethanol to give 12.8 g (50.9%) of product, mp 82.5.degree.-84.degree. C.
Analysis:
Calculated for C.sub.28 H.sub.44 N.sub.2 O.sub.4 : 71.15% C 9.38% H 5.93% N Found: 70.86% C 9.18% H 5.82% N
EXAMPLE 16
erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetami de
To a solution of ethyl erythro-2-acetamido-3-[6-(1-dodecynyl)-2-pyridinyl]-3-hydroxypropionate (20.3 g) in dry tetrahydrofuran (250 ml) 2.0M lithium borohydride:tetrahydrofuran (30 ml) was added at 0.degree., under nitrogen. The reaction mixturewas stirred at room temperature overnight. The mixture was chilled and 1:1-methanol:water (100 ml) was added slowly followed by glacial acetic acid (3.5 ml) in 1:1-methanol:water (50 ml) until a pH of 6.5 was obtained. The solution was stirred at roomtemperature for 2 hrs, the solvents were evaporated, and the residue was azeotroped with methanol (5.times.100 ml). The residue was slurried with 7.5% sodium bicarbonate solution (65 ml) (pH 8.5), extracted into 3:1-chloroform:2-propanol, andconcentrated. The residue was flash chromatographed on silica gel, eluting with 0.5% -methanol:ethyl acetate. The appropriate fractions were collected and evaporated. Recrystallization of the residue from hexane:ethyl acetate/1:1 gave 15.5 g (85.0%)of product, mp 86.degree.-88.degree. C.
Analysis:
Calculated for C.sub.22 H.sub.34 N.sub.2 O.sub.3 : 70.55% C 9.15% H 7.48% N Found: 70.78% C 9.35% H 7.49% N
EXAMPLE 17
Ethyl erythro-2-acetamido-3-(6-decyl-2-pyridinyl)-3-hydroxypropionate
Ethyl erythro-2-acetamido-3-[6-(1-decynyl)-2-pyridinyl]-3-hydroxypropionate (2.7 g) in ethanol (65 ml) was reduced using 5% palladium-on-charcoal (0.7 g) in a Parr hydrogenator at 40 psi of hydrogen. After 2.5 hrs, the catalyst was collected,the filtrate was evaporated, and the residue was recrystallized from ethyl acetate to give 2.11 g (77.6%) of product, mp 67.degree.-68.5.degree. C.
Analysis:
Calculated for C.sub.22 H.sub.36 N.sub.2 O.sub.4 : 67.32% C 9.24% H 7.14% N Found: 66.96% C 9.13% H 7.08% N
EXAMPLE 18
erythro-N-[1-(6-Decyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide
erythro-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}-acetamid e (4.0 g) in ethanol (100 ml) was reduced using 5% palladium-on-charcoal (0.1 g) in a Parr hydrogenator at 40 psi of hydrogen. After two hrs, the catalyst was collected,the solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 3.69 g (91%) of product, mp 94.degree.-96.degree. C.
Analysis:
Calculated for C.sub.20 H.sub.34 N.sub.2 O.sub.3 : 68.54% C 9.78% H 7.99% N Found: 68.36% C 9.72% H 7.94% N
EXAMPLE 19
threo-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-dihydroxypropane
threo-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-diacetyloxy-2-propanyl}acetamide (1.0 g) in ethanol (55 ml) was reduced using 5% palladium-on-charcoal (0.06 g) in a Parr hydrogenator at 40 psi of hydrogen. After two hrs, the catalyst was collected,and the solvent was evaporated to give 0.95 g (94%) of threo-N-[3-(6-decyl-2-pyridinyl)-1,3-diacetyloxy-2-propanyl]acetamide.
The acetamide (0.95 g), hydrazine hydrate (40 ml), and ethanol (20 ml) was heated under reflux for 25 hrs., under nitrogen. The reaction mixture was cooled, water (30 ml) was added, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel eluting with 980:20:2- to970:30:2-trichloromethane:methanol:2N ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was dissolved in ethyl acetate, washed with half-saturated sodium chloride solution, dried, filtered, and the filtrate wasevaporated to give 0.50 g (72%) of product, mp 76.degree.-78.degree. C.
Analysis:
Calculated for C.sub.18 H.sub.32 N.sub.2 O.sub.2 : 70.09% C 10.46% H 9.08% N Found: 70.02% C 10.63% H 8.85% N
EXAMPLE 20
erythro-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-dihydroxypropane
erythro-N-[1-(6-Decyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide (6.0 g), hydrazine hydrate (60 ml), and ethanol (15 ml) were refluxed for 20 hrs., under nitrogen. The reaction mixture was cooled, water (75 ml) was added, and the mixturewas extracted with ethyl acetate. The ethyl acetate layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was combined with 1.44 g from two otherexperiments, and was chromatographed on silica gel eluting with 950:50:3- to 900:100:5-trichloromethane:methanol:2N ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was dissolved in ethyl acetate (150 ml) and thesolution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 5.60 g (79%) of product, mp 52.degree.-55.degree. C.
Analysis:
Calculated for C.sub.18 H.sub.32 N.sub.2 O.sub.2 : 70.09% C 10.46% H 9.08% N Found: 69.63% C 10.29% H 8.87% N
EXAMPLE 21
Ethyl erythro-2-acetamido-3-(6-dodecyl-2-pyridinyl)-3-hydroxypropionate
Ethyl erythro-2-acetamido-3-[6-(1-dodecynyl)-2-pyridinyl]-3-hydroxypropionate (2.0 g) in ethanol (80 ml) containing of 5% palladium-on-carbon (0.06 g) was reduced in a Parr hydrogenator at 40 psi of hydrogen. After two hrs, the catalyst wasfiltered, the filtrate was evaporated, and the residue was recrystallized from ethyl acetate to give 1.42 g (70.3%) of product, mp 71.degree.-73.degree. C.
Analysis:
Calculated for C.sub.24 H.sub.40 N.sub.2 O.sub.4 : 68.54% C 9.59% H 6.66% N Found: 68.74% C 9.46% H 6.69% N
EXAMPLE 22
erythro-N-[1-(6-Dodecyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide
erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetami de (6.05 g) in ethanol (120 ml) containing 5% palladium-on-carbon (0.15 g) was reduced in a Parr hydrogenator at 30 psi of hydrogen. After two hrs, the catalyst wasfiltered, the filtrate was evaporated, and the residue was recrystallized from ethyl acetate to give 5.90 g (96.4%) of product, mp 99.degree.-100.5.degree. C.
Analysis:
Calculated for C.sub.22 H.sub.38 N.sub.2 O.sub.3 : 69.80% C 10.12% H 7.40% N Found: 69.71% C 10.37% H 7.34% N
EXAMPLE 23
erythro-2-Amino-1-(6-dodecyl-2-pyridinyl)-1,3-propanediol
erythro-N-[1-(6-Dodecyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide (3.8 g), hydrazine hydrate (35 ml), and ethanol (20 ml) were refluxed under nitrogen for 24 hrs. The reaction mixture was cooled, water (50 ml) was added, and the mixturewas extracted with chloroform (3.times.65 ml). The extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel, elutingwith 950:50:3-chloroform:methanol:2N ammonium hydroxide. The residue was dissolved in ethyl acetate and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated to give 2.10 g (62%) of product, mp 61.degree.-64.degree. C.
Analysis:
Calculated for C.sub.20 H.sub.36 N.sub.2 O.sub.2 : 71.38% C 10.78% H 8.32% N Found: 71.04% C 10.95% H 8.07% N
EXAMPLE 24
erythro-N-[1-(6-Hexyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide
erythro-N-{1-[6-(1-Hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (5.80 g) in ethanol (125 ml) was hydrogenated using 0.15 g of 5% palladium-on-carbon in a Parr system at 40 psi. After 2.5 hours, the catalyst was collected, thefiltrate was evaporated, and the residue was recrystallized from ethyl acetate to give 5.2 g (88.6%) of product, mp 75.degree.-76.5.degree. C.
Analysis:
Calculated for C.sub.16 H.sub.26 N.sub.2 O.sub.3 : 65.28% C 8.90% H 9.52% N Found: 65.18% C 8.78% H 9.50% N
EXAMPLE 25
N,O,O-Tribenzyloxycarbonyl-erythro-2-amino-1-(6-decyl-2-pyridinyl)-1,3-prop anediol
erythro-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-propanediol (1.50 g), N-benzyloxycarbonyloxysuccinimide (4.00 g) and triethylamine (2.23 ml) in dry tetrahydrofuran (60 ml) was stirred at room temperature for 9 days, under nitrogen. AdditonalN-benzyloxycarbonyloxysuccinimide (4.00 g) was added and stirring was continued for 3 days. The reaction mixture was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate). The appropriate fractions were collected and evaporated to give 1.87 g (54%) of product.
Analysis:
Calculated for C.sub.42 H.sub.50 N.sub.2 O.sub.8 : 70.96% C 7.09% H 3.94% N Found: 71.00% C 6.92% H 3.77% N
EXAMPLE 26
Ethyl erythro-2-acetamido-3-hydroxy-3-[3-(1-undecynyl)phenyl]propionate
To a solution of 3-bromobenzaldehyde (30.3 g) and 1-undecyne (29.5 g) in triethylamine (120 ml) was added bis(triphenylphosphine)palladium(II) chloride (1.9 g) followed by copper(I) iodide (0.25 g). The mixture was stirred in the dark at55.degree. C. for 6 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated to yield 45.8 g of 3-(1-undecynyl)benzaldehyde, as an oil.
A solution of 3-(1-undecynyl)benzaldehyde (23.0 g), acetamidomalonic acid monoethyl ester (15.1 g), and triethylamine (11.2 ml) in dry tetrahydrofuran (150 ml) was stirred at room temperature for 48 hrs, under nitrogen. Additionalacetamidomalonic acid monoethyl ester (7.6 g) and triethylamine (5.6 ml) were added and stirring was continued for 72 hrs. The reaction mixture was evaporated and the residue was purified on a silica gel column, eluting with 2:1-hexane:ethyl acetate togive 13.0 g (41%) of product. The product was dissolved in warm 3:2-ethanol:water and cooled. The precipitate was collected. The filtrate was concentrated and the residue was recrystallized from cyclohexane to give the analytical sample, mp69.degree.-71.degree. C.
Analysis:
Calculated for C.sub.24 H.sub.35 NO.sub.4 : 71.79% C 8.79% H 3.49% N Found: 71.81% C 8.72% H 3.51% N
EXAMPLE 27
Ethyl erythro-2-acetamido-3-[3-(1-dodecynyl)phenyl]-3-hydroxypropionate
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the darkat 55.degree. C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
A solution of 3-(1-dodecynyl)benzaldehyde (7.6 g), acetamidomalonic acid monoethyl ester (5.1 g), and triethylamine (3.8 ml) in dry tetrahydrofuran (35 ml) was stirred at room temperature for 48 hrs, under nitrogen. Additional acetamidomalonicacid monoethyl ester (2.6 g) and triethylamine (1.9 ml) were added and stirring for 72 hr. The mixture was evaporated, and the residue was purified on a silica gel column, eluting with 2:1-hexane:ethyl acetate to give 4.8 g (43%) of product. Theproduct was dissolved in warm 3:2-ethanol:water and cooled. The precipitate was collected. The filtrate was concentrated and the residue was recrystallized from 1:2-ethyl acetate:hexane to provide the analytical sample, mp 80.degree.-82.degree. C.
Analysis:
Calculated for C.sub.25 H.sub.37 NO.sub.4 : 72.26% C 8.97% H 3.37% N Found: 72.34% C 8.74% H 3.38% N
EXAMPLE 28
cis-erythro-N-{1-[6-(1-Dodecenyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}ace tamide
erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetami de (2.05 g) in ethanol (55 ml), 5% palladium-on-barium sulfate (0.02 g), and 0.04 g of quinoline was hydrogenated at atmospheric pressure until one equivalent of hydrogen(ca. 123 ml) was taken up. The catalyst was filtered, the filtrate was evaporated, and the residue (2.1 g) was combined with residue (3.5 g) from similar reactions. The combined residues were chromatographed on silica gel eluting with 1:2- to1:4-hexane:ethyl acetate to give 1.58 g (28%) of product, mp 96.degree.-98.degree. C.
Analysis:
Calculated for C.sub.22 H.sub.36 N.sub.2 O.sub.3 : 70.18% C 9.64% H 7.44% N Found: 70.17% C 9.67% H 7.43% N
EXAMPLE 29
5-(1-Dodecynyl)-2-thiophenecarboxaldehyde
A solution of 1-dodecyne (28.7 g), 5-bromo-2-thiophenecarboxaldehyde (30.0 g) and triethylamine (47.7 g) in dry tetrahydrofuran (75 ml) was degassed and stirred at room temperature under a nitrogen atmosphere. bis(Triphenylphosphine)palladium(II)chloride (two mole percent) followed by copper(I)iodide (one mole percent) was added to the mixture. The mixture was degassed again and stirred at room temperature for three hrs, under nitrogen. The precipitate wascollected and washed with ethyl acetate, and the filtrate was evaporated. The residue was distilled in a kugelrohr (oven temp=175.degree. C./0.1 mm Hg) to give 27.1 g (62%) of product, as a oil. A portion of the oil was purified by flashchromatography (silica; 7:3-hexane-dichloromethane) and dried at 50.degree. C. under vacuum for three hrs to give the analytical sample
Analysis:
Calculated for C.sub.17 H.sub.24 OS: 73.86% C 8.75% H Found: 73.86% C 8.72% H
EXAMPLE 30
Ethyl erythro-2-acetamido-3-[5-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate
A slurry of 5-dodecynyl-2-thiophenecarboxaldehyde (31.8 g), acetamidomalonic acid monoethyl ester (21.7 g), and dry tetrahydrofuran (150 ml) was degassed and cooled to 0.degree. C. Triethylamine (5% excess) was added, the solution was degassed,and the reaction mixture was stirred at room temperature for 2 days, under nitrogen. Additional acetamidomalonic acid monoethyl ester (21.7 g) and triethylamine (5% excess) were added, and the reaction mixture was stirred at room temperature for 5 days,under nitrogen. The mixture was evaporated, and the residue was purified by flash chromatography (silica, 1:1-ethyl acetate:hexanes). The appropriate fractions were c | | | |
